Substituted imidazo[1,2-a]pyridines as PDE-10 inhibitors

ABSTRACT

Provided herein are cyclic nucleotide phosphodiesterase inhibitors of Formula (I) of claim 1, and pharmaceutical compositions thereof, useful for the treatment of, for example, central nervous system and metabolic diseases and disorder.

I. CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to and is a continuation of pendingU.S. patent application Ser. No. 14/884,397, file Oct. 15, 2015, whichin turn claims priority to and is a divisional of U.S. patentapplication Ser. No. 14/298,691, filed Jun. 6, 2014, and patented asU.S. Pat. No. 9,249,162 on Sep. 25, 2014; which in turn claims priorityto and is a divisional of U.S. patent application Ser. No. 13/347,541,filed Jan. 10, 2012, and patented as U.S. Pat. No. 8,765,760 on Jul. 1,2014, which in turn claims benefit from U.S. Provisional PatentApplication Ser. No. 61/431,769 filed Jan. 11, 2011, all of which arehereby incorporated by reference in their entireties.

II. FIELD

Provided herein are heteroaryl compounds useful for treating variousdisorders or diseases, such as disorders or diseases of the centralnervous system and metabolic disorders. Also provided herein arecompositions comprising the compounds, and methods of use thereof.

III. BACKGROUND

Central nervous system (CNS) disorders affect a wide range of thepopulation with differing severity. For example, schizophrenia is apsychopathological disorder of unknown origin, which usually appears forthe first time in early adulthood and is marked by characteristics, suchas, psychotic symptoms, phasic progression and development, anddeterioration in social behavior and professional capability.Characteristic psychotic symptoms include disorders of thought content(e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence, orincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and inter-human relationships,and psychomotoric disorders (e.g., catatonia). Other symptoms are alsoassociated with this disorder. See, e.g., Diagnostic and StatisticalManual of Mental Disorders, 4^(th) Ed., American Psychiatric Association(1997) (DSM-IV™).

Schizophrenia can be classified into various subgroups. For example, theparanoid type is characterized by delusions and hallucinations andabsence of thought disorder, disorganized behavior, and affectiveflattening. The disorganized type, also named hebephrenic schizophrenia,is characterized by the presence of both thought disorder and affectiveflattening. The catatonic type is characterized by prominent psychomotordisturbances, including symptoms of catatonic stupor and waxyflexibility. In the undifferentiated type, psychotic symptoms arepresent but the criteria for paranoid, disorganized, or catatonic typeshave not been met.

The symptoms of schizophrenia normally manifest themselves in threebroad categories, i.e., positive, negative and cognitive symptoms.Positive symptoms are those that represent an excess of normalexperiences, such as hallucinations, disorganized speech, and delusions.Negative symptoms are those where the patient suffers from a lack ofnormal experiences, such as anhedonia, lack of motivation, inability toexperience pleasure, and lack of social interaction. The cognitivesymptoms relate to cognitive impairment in schizophrenics, such as lackof sustained attention, impairment of memory, and deficits in decisionmaking. The current anti-psychotics are somewhat effective in treatingthe positive symptoms but are less effective in treating the negative orcognitive symptoms. For instance, the current typical or atypicalanti-psychotics do not address cognitive or negative symptoms ofschizophrenia, and only treat the positive symptoms in approximately 40%of patients.

Cognitive impairments include a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving, e.g., executive function, speed of processing and/or socialcognition. In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, difficulties in integratingthoughts, feelings and behavior, or difficulties in extinction ofirrelevant thoughts.

Agitation is a well-recognized behavioral disorder with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension, and uncooperativeness. Agitation is common in the elderly andoften associated with dementia such as those caused by Alzheimer'sdisease, Parkinson's disease, and Huntington's disease, and by diseasesthat affect blood vessels, such as stroke or multi-infarct dementia,which is caused by multiple strokes in the brain. An estimated fivepercent of people aged 65 and older and up to 20 percent of those aged80 and older are affected by dementia. Of these sufferers, nearly halfexhibit behavioral disturbances, such as agitation, wandering, andviolent outbursts. Agitated behaviors can also be manifested incognitively intact elderly people and by those with psychiatricdisorders other than dementia.

Dementia is characterized by several cognitive impairments includingsignificant memory deficit and can stand alone, or be an underlyingcharacteristic feature of a variety of diseases, including but notlimited to, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and multiple sclerosis.

Thus, there remains a great need for effective treatments of various CNSdisorders.

Cyclic nucleotide phosphodiesterases (PDEs) are a super family ofenzymes encoded by twenty-one genes, and are subdivided into elevenknown families based on structure and function. PDEs are modular enzymeshaving a catalytic domain in the C-terminal portion of the protein andregulatory elements in the N-terminal portion. PDEs hydrolyze thephosphodiester bond of cyclic nucleotides, e.g., cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP),converting them into the corresponding monophosphates. cAMP and cGMPfunction as intracellular second messengers regulating a wide range ofintracellular processes. For instance, in neurons cAMP and cGMP activatecyclic-nucleotide-dependent kinases and the subsequent phosphorylationof proteins involved in acute regulation of synaptic transmission and inneuronal differentiation and survival. PDEs are therefore importantregulators of a wide variety of physiological processes. PDEs areexpressed differentially throughout the organism and cyclic nucleotidesignaling is highly compartmentalized within individual cells. Thus,different PDE isozymes can serve distinct physiological functions.Compounds that can selectively inhibit distinct PDE families or isozymesmay offer additional therapeutic benefits, fewer side effects, or both.

PDE-10 was first reported in 1999 (Soderling et al., Proc. Natl. Acad.Sci., 1999, 96, 7071-76; Loughney et al., Gene, 1999, 234, 109-17;Fujishige et al., J. Biol. Chem., 1999, 274, 18438-45). Homologyscreening revealed mouse PDE-10A as the first member of the PDE-10family of enzymes. The human PDE-10 sequence is highly homologous toboth the rat and mouse PDE-10 enzymes. The PDE-10 family of enzymes hasa lower degree of sequence homology as compared to previously identifiedPDE families. PDE-10 can hydrolyze both cAMP (K_(m)=0.26 μM) and cGMP(K_(m)=7.2 μM), and has a five-fold greater V_(max) for cGMP than forcAMP.

PDE-10A is primarily expressed in the brain, also found in testes.PDE-10A mRNA and protein are abundant in brain tissues, and are mainlydetected at high levels in the medium spiny neurons (MSN) of thestriatum, a distribution conserved across mammalian species. Thestriatal MSNs provide input to the basal ganglia circuit, affectingaction selection and execution, and suppressing undesired responses tosensory stimuli. PDE-10A has become an emerging target for thedevelopment of new anti-psychotics. Inhibitors of PDE-10A have beenshown to increase cAMP and cGMP levels in striatal tissue and havedemonstrated efficacy against not only positive but also negative andcognitive symptoms in animal models of schizophrenia. PDE-10A is alsouseful in treating metabolic disorders, such as diabetes, obesity, andmetabolic syndrome.

Citation of any references in this Section of the application is not tobe construed as an admission that such reference is prior art to thepresent application.

IV. SUMMARY

Provided herein are compounds of formula (I), or pharmaceuticallyacceptable salts or stereoisomers thereof:A-L-B  (I),wherein A, L, and B are defined herein elsewhere. The compounds areuseful for treating various diseases or disorders, such as CNS disordersand metabolic disorders.

Also provided herein are compositions and dosage forms comprising, acompound provided herein, and one or more pharmaceutically acceptableexcipient(s). Compositions and dosage forms provided herein may furthercomprise one or more additional active ingredients.

Also provided herein are methods for the treatment, prevention, and/ormanagement of various disorders, such as a CNS disorder or a metabolicdisorder, e.g., the treatment, prevention, and/or amelioration of one ormore symptoms of a disorder, using the compounds and compositionsprovided herein. In one embodiment, the disorders provided hereininclude, but are not limited to, schizophrenia, psychosis, cognitivedisorders, mood disorders, attention deficit disorders, andneurodegenerative diseases. In one embodiment, the disorders include,but are not limited to, neurological disorder, schizophrenia,schizophrenia-related disorder, schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoaffectivedisorder, schizophreniform disorder, paraphrenia, paranoid personalitydisorder, schizoid personality disorder, schizotypal personalitydisorder, delusional disorder, psychosis, disease having a psychosiscomponent, psychotic disorder, brief psychotic disorder, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder,substance-induced psychotic disorder (e.g., cocaine, alcohol,amphetamine), psychotic disorder due to a general medical condition,psychoaffective disorder, aggression, delirium, excitative psychosis,Tourette's syndrome, manic disorder, organic psychosis, NOS psychosis,convulsion, seizure, agitation, posttraumatic stress disorder, behaviordisorder, neurodegenerative disease, Huntington's disease, Alzheimer'sdisease, Parkinson's disease, dyskinesia, dementia, mood disorder,bipolar disorder, anxiety, depression, major depressive disorder,unipolar depression, treatment resistant depression, dysthymia,affective disorder, seasonal affective disorder, obsessive-compulsivedisorder, attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD), vertigo, pain, neuropathic pain,sensitization accompanying neuropathic pain, inflammatory pain,fibromyalgia, migraine, cognitive impairment, cognitive impairmentassociated with schizophrenia, cognitive deficit in Alzheimer's disease,cognitive deficit in Parkinson's disease, movement disorder, restlessleg syndrome (RLS), multiple sclerosis, sleep disorder, substance abuseor dependency (e.g., nicotine, cocaine), addiction, eating disorder,autism, obesity, undesirable weight retention or weight gain, metabolicsyndrome, diabetes, non-insulin dependent diabetes, impaired glucosetolerance, and hyperglycemia.

In one embodiment, provided herein is a method of treating, preventing,and/or managing schizophrenia or related disorders, including but notlimited to, schizoaffective disorder, schizophreniform disorder,paraphrenia, paranoid personality disorder, schizoid personalitydisorder, and schizotypal personality disorder; a disease having apsychosis component, including but not limited to, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder, andsubstance-induced psychotic disorder; cognitive impairment, includingbut not limited to, cognitive impairment associated with schizophrenia,cognitive deficit in Alzheimer's disease, and cognitive deficit inParkinson's disease; mood disorder, including but not limited to,bipolar disorder; attention deficit disorder, including but not limitedto attention deficit hyperactive disorder; neurodegenerative disease,including but not limited to, Huntington's disease; or depression,including but not limited to, major depressive disorder, unipolardepression, and treatment resistant depression. In one embodiment,provided herein is a method of treating, preventing, and/or managing adisorder provided herein elsewhere (e.g., a CNS disorder or a metabolicdisorder), in a subject, such as a mammal, e.g., human, rodent (e.g.,mice and rats), cat, dog, and non-human primate, among others. In oneembodiment, provided herein is a method of treating, preventing, and/orameliorating one or more symptoms associated with a disorder providedherein elsewhere (e.g., a CNS disorder or a metabolic disorder), in asubject, such as a mammal, e.g., human, rodent (e.g., mice and rats),cat, dog, and non-human primate, among others. In one embodiment, themethod comprises contacting a compound provided herein with a PDEenzyme. In one embodiment, the method comprises contacting a compoundprovided herein with a PDE enzyme expressed in the central nervoussystem. In one embodiment, the method comprises contacting a compoundprovided herein with PDE-10A. In one embodiment, the method comprisescontacting a cell with a compound provided herein. In an exemplaryembodiment, the cell is a brain cell, such as, e.g., a MSN cell, aneuronal cell, or a glial cell.

V. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. All publications and patents referred to herein areincorporated by reference herein in their entireties.

A. Definitions

As used in the specification and the accompanying claims, the indefinitearticles “a” and “an” and the definite article “the” include plural aswell as singular referents, unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may be optionally substituted with one or moresubstituents. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6(C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ and branched C₁₋₆ alkylgroups are also referred as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl (including allisomeric forms, e.g., n-propyl, isopropyl), butyl (including allisomeric forms, e.g., n-butyl, isobutyl, t-butyl), pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In certain embodiments, the alkyl isoptionally substituted as described herein elsewhere. In someembodiments, the alkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenyl groups include, but are not limited to, ethenyl, propen-1-yl,propen-2-yl, allyl, butenyl, and 4-methylbutenyl. In certainembodiments, the alkenyl is optionally substituted as described hereinelsewhere. In some embodiments, the alkenyl is optionally substitutedwith one or more halo.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. The term “alkynyl” also encompasses both linear andbranched alkynyl, unless otherwise specified. In certain embodiments,the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groups include, but arenot limited to, ethynyl (—C≡CH) and propargyl (—CH₂C≡CH). For example,C₂₋₆ alkynyl refers to a linear unsaturated monovalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated monovalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, thealkynyl is optionally substituted as described herein elsewhere. In someembodiments, the alkynyl is optionally substituted with one or morehalo.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic fully or partially saturated bridged and/ornon-bridged hydrocarbon radical or ring system, which may be optionallysubstituted with one or more substituents. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12(C₃₋₁₂), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,decalinyl, and adamantyl. In certain embodiments, the cycloalkyl isoptionally substituted as described herein elsewhere. In someembodiments, the cycloalkyl is optionally substituted with one or morehalo.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain, consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, heteroatoms selected from the group consisting of O, N, Si, andS, and wherein the nitrogen and sulfur atoms are optionally oxidized andthe nitrogen heteroatom can optionally be quaternized. In oneembodiment, the heteroatom(s) O and N can be placed at any interiorposition of the heteroalkyl group. In one embodiment, the heteroatom(s)S and Si can be placed at any position of the heteroalkyl group (e.g.,interior or terminal position), including the position at which thealkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms can be consecutive, such as,for example, —CH₂—NH—O—CH₃ and —CH₂—O—Si(CH₃)₃. In certain embodiments,the heteroalkyl is optionally substituted as described herein elsewhere.In some embodiments, the heteroalkyl is optionally substituted with oneor more halo.

As used herein, and unless otherwise specified, the term “alkoxyl” or“alkoxy” refers to a stable straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, O atoms, wherein at least one O atom is at the position where thealkoxyl or alkoxy group is attached to the remainder of the molecule.Examples of alkoxyl include, but are not limited to, —O—CH₃, —O—CF₃,—O—CH₂—CH₃, —O—CH₂—CH₂—CH₃, —O—CH—(CH₃)₂, and —O—CH₂—CH₂—O—CH₃. In oneembodiment, the alkoxyl is optionally substituted as described hereinelsewhere. In some embodiments, the alkoxyl is optionally substitutedwith one or more halo.

As used herein, and unless otherwise specified, the term “aminoalkyl” or“alkylamino” refers to a stable straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, N atoms, wherein at least one N atom is at the position where theaminoalkyl or alkylamino group is attached to the remainder of themolecule. Examples of aminoalkyl include, but are not limited to,—NH—CH₃, —N(CH₃)₂, —NH—CH₂—CH₃, —N(CH₃)—CH₂—CH₃, —NH—CH—(CH₃)₂, and—NH—CH₂—CH₂—N(CH₃)₂. In one embodiment, the aminoalkyl is optionallysubstituted as described herein elsewhere. In some embodiments, theaminoalkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “aryl” refersto an optionally substituted monocyclic or multicyclic radical or ringsystem that contains at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10ring atoms. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. In certain embodiments, aryl also refers tobicyclic, tricyclic, or tetracyclic carbon rings, where one of the ringsis aromatic and the other(s) of the rings may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where atleast one of the rings is aromatic and one or more of the ring(s) is/aresaturated or partially unsaturated containing one or more heteroatomsindependently selected from O, S, and N. In certain embodiments, thearyl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl. Anexample of aralkyl includes, but is not limited to, benzyl. In certainembodiments, both alkyl and aryl may be optionally substituted with oneor more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term“heteroarylalkyl” or “heteroaralkyl” refers to a monovalent alkyl groupsubstituted with heteroaryl. In certain embodiments, both alkyl andheteroaryl may be optionally substituted with one or more substituentsas described herein elsewhere.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to an optionally substituted monocyclic or multicyclic radical orring system which contains at least one aromatic ring having one or moreheteroatoms independently selected from O, S, and N. In one embodiment,each ring of a heteroaryl group can contain one or two O atoms, one ortwo S atoms, and/or one to four N atoms, provided that the total numberof heteroatoms in each ring is four or less and each ring contains atleast one carbon atom. In certain embodiments, the heteroaryl has from 5to 20, from 5 to 15, or from 5 to 10 ring atoms. In certain embodiments,heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings,where one of the rings is aromatic having one or more heteroatomsindependently selected from O, S, and N, and the other(s) of the ringsmay be saturated, partially unsaturated, or aromatic and may becarbocyclic or contain one or more heteroatoms independently selectedfrom O, S, and N. Examples of monocyclic heteroaryl groups include, butare not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, periinidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionally substitutedmonocyclic or multicyclic radical or ring system which contains at leastone non-aromatic ring having one or more heteroatoms independentlyselected from O, S, and N. In certain embodiments, the heterocyclyl orheterocycloalkyl group has from 3 to 20, from 3 to 15, from 3 to 10,from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certainembodiments, the heterocyclyl or heterocycloalkyl is a monocyclic,bicyclic, tricyclic, or tetracyclic ring system, which may include afused or bridged ring system, and in which the nitrogen or sulfur atomsmay be optionally oxidized, the nitrogen atoms may be optionallyquaternized, the ring carbon atoms may be optionally substituted withoxo, and some rings may be partially or fully saturated, or aromatic.The heterocycloalkyl or heterocyclyl may be attached to the mainstructure at a heteroatom or a carbon atom which results in the creationof a stable compound. Examples include, but are not limited to,azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocotimarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl orheterocycloalkyl ring contains one or more O, the heterocyclyl orheterocycloalkyl may also be referred to as “cycloalkoxyl.” In certainembodiments, the heterocyclyl or heterocycloalkyl is optionallysubstituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and iodine.

As used herein, and unless otherwise specified, the term “hydrogen”encompasses proton (¹H), deuterium (²H), tritium (³H), and/or mixturesthereof. In a compound described herein, one or more positions occupiedby hydrogen may be enriched with deuterium and/or tritium. Suchisotopically enriched analogs may be prepared from suitable isotopicallylabeled starting material obtained from a commercial source or preparedusing known literature procedures.

As used herein, and unless otherwise specified, the term “optionallysubstituted” is intended to mean that a group, such as an alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxyl, aminoalkyl, aryl,aralkyl, heteroaralkyl, heteroaryl, or heterocyclyl, may be substitutedwith one or more substituents independently selected from, e.g., (a)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q¹; and (b) halo, cyano (—CN), nitro (—NO₂), oxo (═O),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹. As used herein,all groups that can be substituted are “optionally substituted,” unlessotherwise specified.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, oxo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids; or from pharmaceutically acceptable non-toxic bases,including inorganic bases and organic bases. In one embodiment, suitablenon-toxic acids include, but are not limited to, acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, prop ionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

In certain embodiments, as used herein, and unless otherwise specified,“optically active” and “enantiomerically active” refer to a collectionof molecules, which has an enantiomeric excess of no less than about50%, no less than about 70%, no less than about 80%, no less than about90%, no less than about 91%, no less than about 92%, no less than about93%, no less than about 94%, no less than about 95%, no less than about96%, no less than about 97%, no less than about 98%, no less than about99%, no less than about 99.5%, or no less than about 99.8%. In certainembodiments, the compound comprises about 95% or more of the desiredenantiomer and about 5% or less of the less preferred enantiomer basedon the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of a pharmaceutical formulation, and suitable for usein contact with the tissue or organ of humans and animals withoutexcessive toxicity, irritation, allergic response, immunogenicity, orother problems or complications, commensurate with a reasonablebenefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,—CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, orameliorating one or more symptoms of a condition, disorder, or disease.As used herein, “active ingredient” and “active substance” may be anoptically active isomer of a compound described herein.

As used herein, and unless otherwise specified, the terms “drug” and“therapeutic agent” refer to a compound, or a pharmaceutical compositionthereof, which is administered to a subject for treating, preventing,managing, or ameliorating one or more symptoms of a condition, disorder,or disease.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of disease or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, “amelioration” of thesymptoms of a particular disorder by administration of a particularpharmaceutical composition refers to any lessening, whether permanent ortemporary, lasting or transient, that can be attributed to or associatedwith the administration of the composition.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human.

As used herein, and unless otherwise specified, the term “neurologicaldisorder” refers to any condition of the central or peripheral nervoussystem of a mammal. The term “neurological disorder” includes, but isnot limited to, neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatricdiseases (e.g., schizophrenia and anxieties, such as general anxietydisorder), and affective disorders (e.g., depression and attentiondeficit disorder). Exemplary neurological disorders include, but are notlimited to, MLS (cerebellar ataxia), Huntington's disease, Downsyndrome, multi-infarct dementia, depression (e.g., major depressivedisorder, dysthymia, and bipolar depressive disorder), dementias,movement disorders, psychoses, alcoholism, post-traumatic stressdisorder and the like. “Neurological disorder” also includes anycondition associated with the disorder. For instance, a method oftreating a neurodegenerative disorder includes methods of treating lossof memory and/or loss of cognition associated with a neurodegenerativedisorder. An exemplary method would also include treating or preventingloss of neuronal function characteristic of neurodegenerative disorder.

As used herein, and unless otherwise specified, the terms “psychosis,”“schizophrenia,” “obsessive-compulsive disorder,” “substance abuse,”“anxiety,” “eating disorders,” “migraine,” and other CNS disordersdescribed herein elsewhere are used herein in a manner consistent withtheir accepted meanings in the art. See, e.g., Diagnostic andStatistical Manual of Mental Disorders, 4^(th) Ed., American PsychiatricAssociation (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “affectivedisorder” includes depression, attention deficit disorder, attentiondeficit disorder with hyperactivity, bipolar and manic conditions, andthe like. The terms “attention deficit disorder” (ADD) and “attentiondeficit disorder with hyperactivity” (ADDH), or attentiondeficit/hyperactivity disorder (AD/HD), are used herein in accordancewith the accepted meanings as found in the Diagnostic and StatisticalManual of Mental Disorders, 4^(th) Ed., American Psychiatric Association(1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “depression”includes all forms of depression including, but not limited to, majordepressive disorder (MDD), bipolar disorder, seasonal affective disorder(SAD), dysthymia, and treatment resistant depression. “Major depressivedisorder” is used herein interchangeably with “unipolar depression” and“major depression.” “Depression” may also include any condition commonlyassociated with depression, such as all forms of fatigue (e.g., chronicfatigue syndrome) and cognitive deficits.

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. The term “pain,” asused herein, refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (See, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia. In addition, The term “pain” includespain resulting from dysfunction of the nervous system: organic painstates that share clinical features of neuropathic pain and possiblecommon pathophysiology mechanisms, but are not initiated by anidentifiable lesion in any part of the nervous system.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

As used herein, and unless otherwise specified, the terms “overweight”and “obese” refer to adult persons 18 years or older having a greaterthan ideal body weight (e.g., greater than ideal body fat) that can bemeasured by the body mass index (BMI), which is generally correlatedwith total body fat and the relative risk of suffering from prematuredeath or disability due to diseases as a consequence of the overweightor obese condition. BMI is calculated by weight in kilograms divided byheight in meters squared (kg/m²), or alternatively by weight in pounds,multiplied by 703, divided by height in inches squared (lbs×703/in²).Overweight individuals typically have a BMI of between about 25 andabout 29, whereas obese individuals typically have a BMI of about 30 ormore (see, e.g., National Heart, Lung, and Blood Institute, ClinicalGuidelines on the Identification, Evaluation, and Treatment ofOverweight and Obesity in Adults, The Evidence Report, Washington, D.C.,U.S. Department of Health and Human Services, NIH publication no.98-4083, 1998). Other means for indicating excess body weight, excessbody fat, and obesity include direct measure of body fat and/orwaist-to-hip ratio measurements.

As used herein, and unless otherwise specified, the term “metabolicsyndrome” is used according to its usual meaning in the art. TheAmerican Heart Association characterizes metabolic syndrome as having atleast three or more of the following symptoms: 1) elevated waistcircumference [>102 cm (40 inches) in men; >88 cm (35 inches) in women];2) elevated triglycerides [≥150 mg/dL (>1.695 mmol/L) or drug treatmentfor elevated triglycerides]; 3) reduced HDL cholesterol [<40 mg/dL(1.036 mmol/L) in men; <50 mg/dL (1.295 mmol/L) in women; or drugtreatment for reduced HDL-C]; 4) elevated blood pressure [≥130/85 mmHgor drug treatment for hypertension]; and 5) elevated fasting glucose[≥110 mg/dL or drug treatment for elevated glucose]. According to theWorld Health Organization, metabolic syndrome includes individualssuffering from diabetes, impaired glucose tolerance, impaired fastingglucose, or insulin resistance plus two or more of the followingsymptoms: 1) high blood pressure [≥160/90 mmHg]; 2) hyperlipdemia[triglyceride concentration ≥150 mg/dL (1.695 mmol/L) and/or HDLcholesterol <35 mg/dL (0.9 mmol/L) in men and <39 mg/dL (1.0 mmol/L) inwomen]; 3) central obesity [waist-to-hip ratio of >0.90 for menand >0.85 for women and/or BMI >30 kg/m²]; and 4) microalbuminuria[urinary albumin excretion rate ≥20 μg/min or an albumin-to-creatinineratio ≥20 mg/kg).

B. Compounds

In one embodiment, provided herein is a compound of formula (I):A-L-B  (I),or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

L is —(C(R¹⁰)₂)_(m)—, —CR¹⁰═CR¹⁰—,

—K—C(R¹⁰)₂—, —C(R¹⁰)₂—K—, or —S—;

K is —NR¹¹—, —O—, or —S—;

m is 2 or 3;

A is

X is (i) CR¹ or N; or (ii) O or NR²;

each Y is independently N or CR³;

each Z is independently N or C;

provided that A contains 1, 2, 3, or 4 nitrogen ring atoms;

B is

B¹ is O, S, or NR⁸;

B² is CR⁹ or N;

R¹ is hydrogen, halo, cyano, alkyl, alkenyl, alkoxyl, aminoalkyl,heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, amino, amido,carbonyl, thiol, sulfinyl, or sulfonyl;

R² is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl;

each R³ is independently (i) hydrogen, halo, cyano, alkyl, alkenyl,alkoxyl, aminoalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, or sulfonyl; or(ii) two adjacent occurrences of R³ together with the atoms to whichthey are attached form an aryl or heteroaryl ring;

R⁴ and R⁵ together with the atoms to which they are attached form amonocyclic or multicyclic aryl, heteroaryl, cycloalkyl, or heterocyclylring;

R⁶ is hydrogen, halo, cyano, alkyl, alkenyl, alkoxyl, aminoalkyl,heteroalkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, or sulfonyl;

R⁷ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl;

R⁸ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl;

R⁹ is hydrogen, halo, cyano, alkyl, alkenyl, alkoxyl, aminoalkyl,heteroalkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, or sulfonyl;

each R¹⁰ is independently hydrogen, halo, or alkyl; and

each R¹¹ is hydrogen or alkyl.

In one embodiment, L is —(C(R¹⁰)₂)_(m)— or —CR¹⁰═CR¹⁰—. In oneembodiment, each R¹⁰ is independently hydrogen or methyl. In oneembodiment, R¹⁰ is hydrogen. In one embodiment, at least one R¹⁰ ismethyl. In one embodiment, at least two occurrences of R¹⁰ are methyl.In one embodiment, at least one R¹⁰ is methyl and the other one or moreR¹⁰ is/are hydrogen. In one embodiment, L is —(CH₂)_(m)—. In oneembodiment, L is —CH═CH—. In one embodiment, L is —CH₂—CH₂—,—CH(Me)-CH₂—, —CH₂—CH(Me)-, —CH₂—CH₂—CH₂—, or —CH═CH—. In oneembodiment, L is —CH₂—CH₂—, —CH(Me)-CH₂—, or —CH₂—CH(Me)-. In oneembodiment, L is —CH(Me)-CH₂— or —CH₂—CH(Me)-. In one embodiment, L is—CH₂—CH₂—. In one embodiment, L is —CH₂—CH₂—CH₂—. In specificembodiments, m is 2. In specific embodiments, in is 3.

In one embodiment, L is

(i.e., a cyclopropylene linker). In one embodiment, L istrans-cyclopropylene. In one embodiment, L is cis-cyclopropylene.

In one embodiment, L is —(C(R¹⁰)₂)_(m)— or

In one embodiment, L is —NR¹¹—C(R¹⁰)₂—, —O—C(R¹⁰)₂—, —S—C(R¹⁰)₂—,—C(R¹⁰)₂—NR¹¹—, —C(R¹⁰)₂)—O—, —C(R¹⁰)₂—S—, or —S—. In one embodiment,each R¹⁰ and R¹¹ is independently hydrogen or methyl. In one embodiment,L is —NR¹¹—CH₂—, —O—CH₂—, —S—CH₂—, —CH₂—NR¹¹—, —CH₂—O—, —CH₂—S—, or —S—.In one embodiment, each R¹¹ is independently hydrogen or methyl.

In one embodiment, A contains from 1 to 2, from 1 to 3, from 1 to 4,from 2 to 3, from 2 to 4, or from 3 to 4 nitrogen ring atoms. In oneembodiment, A contains one nitrogen ring atom. In one embodiment, Acontains two nitrogen ring atoms. In one embodiment, A contains threenitrogen ring atoms. In one embodiment, A contains four nitrogen ringatoms.

In one embodiment, A is:

wherein Y is defined herein elsewhere.

In one embodiment, A is:

wherein Y and R¹ are defined herein elsewhere. In one embodiment, R¹ isH, halo, cyano, methyl, or CF₃.

In one embodiment, A is:

wherein Y is defined herein elsewhere.

In one embodiment, A is:

wherein Y is defined herein elsewhere.

In one embodiment, A is:

wherein R³ and Y are defined herein elsewhere.

In one embodiment, A is:

wherein R³ and Y are defined herein elsewhere.

In one embodiment, A is:

wherein R³ is defined herein elsewhere.

In one embodiment, A is:

wherein R³ is defined herein elsewhere.

In one embodiment, A is:

In one embodiment, A is:

wherein R¹, R³, and Y are defined herein elsewhere. In one embodiment,R¹ is H, halo, cyano, methyl, or CF₃.

In one embodiment, A is:

wherein R¹ and R³ are defined herein elsewhere.

In one embodiment, A is:

wherein R³ is defined herein elsewhere.

In one embodiment, A is:

wherein R³ is defined herein elsewhere.

In one embodiment, A is:

wherein R³ is defined herein elsewhere.

In one embodiment, A is optionally substituted with up to threesubstituents. In one embodiment, up to three occurrences of R³substituting A are not hydrogen.

In one embodiment, each R³ is independently hydrogen, halo, cyano,(C₁-C₆)alkyl, (C₁-C₆)alkoxyl, (C₁-C₆)aminoalkyl, (C₁-C₆)heteroalkyl,aryl, or heteroaryl. In one embodiment, each R³ is independentlyhydrogen, halo, cyano, (C₁-C₆)alkyl, or (C₁-C₆)alkoxyl. In oneembodiment, each R³ is independently hydrogen, halo (e.g., F, Cl, orBr), cyano, methyl, ethyl, methoxyl, ethoxyl, CF₃, or OCF₃. In oneembodiment, each R³ is independently hydrogen, F, Cl, cyano, methyl,ethyl, methoxyl, ethoxyl, CF₃, or OCF₃. In one embodiment, each R³ isindependently hydrogen, F, Cl, methyl, ethyl, or CF₃. In one embodiment,each R³ is independently hydrogen, Cl, methyl, or CF₃. In oneembodiment, each R³ is independently hydrogen or methyl. In oneembodiment, two adjacent occurrences of R³ together with the atoms towhich they are attached form a 5- or 6-membered aryl to heteroaryl ring(e.g., optionally substituted benzene or pyridine).

In one embodiment, X is CR¹ or N. In one embodiment, X is O, S, or NR².In one embodiment, X is O or NR². In one embodiment, R¹ is hydrogen ormethyl. In one embodiment, R² is hydrogen or methyl.

In one embodiment, Y is N. In one embodiment, Y is CR³. In oneembodiment, each R³ is independently hydrogen, methyl, ethyl, chloro, orCF₃. In one embodiment, each R³ is independently hydrogen or methyl. Oneoccurrence of Y may be the same or different from another occurrence ofY.

In one embodiment, Z is N. In one embodiment, Z is C. One occurrence ofZ may be the same or different from another occurrence of Z. In oneembodiment, one of the two occurrences of Z is C and the other is N. Inone embodiment, one of the two occurrences of Z is N. In one embodiment,at least one of the two occurrences of Z is N. In one embodiment, bothoccurrences of Z is C.

In one embodiment, B is

wherein B¹, B², R⁴, and R⁵ are defined herein elsewhere. In oneembodiment, R⁴ and R⁵ together form a monocyclic ring and B is abicyclic ring system. In one embodiment, R⁴ and R⁵ together form amulticyclic ring and B is a tricyclic ring system.

In one embodiment, B¹ is —NR⁸ and B² is CR⁹ or N.

In one embodiment, B¹ is NH or NCH₃. In one embodiment, B² is CH or N.

In one embodiment, B is a bicyclic ring. In one embodiment, B is atricyclic ring. In one embodiment, B contains from 1 to 6, from 1 to 5,from 1 to 4, from 2 to 6, from 2 to 5, from 2 to 4, from 2 to 3, from 3to 4, or from 3 to 5 nitrogen ring atoms. In one embodiment, B containsone nitrogen ring atom. In one embodiment, B contains two nitrogen ringatoms. In one embodiment, B contains three nitrogen ring atoms. In oneembodiment, B contains four nitrogen ring atoms. In one embodiment, Bcontains five nitrogen ring atoms. In one embodiment, B contains sixnitrogen ring atoms.

In one embodiment, B is optionally substituted with up to one, up totwo, up to three, up to four, up to five, or up to six substituents. Inone embodiment, B is optionally substituted with one or more halo,cyano, or methyl.

In one embodiment, B is a bicyclic ring system. In one embodiment, B is:

wherein R⁹ is defined herein elsewhere: and each R¹² is independentlyhydrogen, halogen, cyano, —O, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴,—C(O)NR¹³R¹⁴, —C(O)R¹³, C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³,—S(O)₂NR¹³R¹⁴, alkyl, heteroalkyl, cycloalkyl, aralkyl, heteroaralkyl,aryl, heteroaryl, or heterocyclyl; wherein each R¹³ and R¹⁴ isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, or heterocyclyl; or when R¹³ and R¹⁴are both attached to one nitrogen atom, R¹³ and R¹⁴ together with thenitrogen atom to which they are attached form a 3 to 10 membered ring.

In one embodiment, B is a tricyclic ring system. In one embodiment, Bis:

wherein R⁸ is defined herein elsewhere; each R¹² is independentlyhydrogen, halogen, cyano, ═O, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴,—C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³,—S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, alkyl, heteroalkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, or heterocyclyl; wherein each R¹³ andR¹⁴ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, or heterocyclyl; or when R¹³ and R¹⁴are both attached to one nitrogen atom, R¹³ and R¹⁴ together with thenitrogen atom to which they are attached form a 3 to 10 membered ring;and Ring C is a 5- or 6-membered heteroaryl ring or a 5- to 7-memberedcycloalkyl or heterocyclyl ring. In one embodiment, Ring C is a 5- or6-membered heteroaryl ring (e.g., an optionally substituted pyridine,pyrimidine, pyrazine, pyridazinc, thiophene, furan, pyrrole, imidazole,pyrazole, oxazole, isoxazole, thiazole, or isothiazole ring). In anotherembodiment, Ring C is a 5- to 7-membered cycloalkyl or heterocyclyl ring(e.g., an optionally substituted cyclohexene or dihydrofuran ring). Insome embodiments, the heterocyclyl ring contains one to twoheteroatom(s) independently selected from N, O, and S. In yet anotherembodiment, Ring C is a 6-membered aryl ring (e.g., an optionallysubstituted benzene ring). In one embodiment, Ring C is optionallysubstituted with one or more R¹², wherein R¹² is defined hereinelsewhere. In specific embodiments, R⁸ is hydrogen or methyl. Inspecific embodiments, R¹² is hydrogen.

In one embodiment, B is:

wherein R⁸ and R¹² are defined herein elsewhere.

In one embodiment, B is:

wherein R⁹ is defined herein elsewhere; each R¹² is independentlyhydrogen, halogen, cyano, ═O, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴,—C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³,—S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, alkyl, heteroalkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, or heterocyclyl; wherein each R¹³ andR¹⁴ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, or heterocyclyl; or when R¹³ and R¹⁴are both attached to one nitrogen atom, R¹³ and R¹⁴ together with thenitrogen atom to which they are attached form a 3 to 10 membered ring;and Ring C is a 5- or 6-membered heteroaryl ring or a 5- to 7-memberedcycloalkyl or heterocyclyl ring. In one embodiment, Ring C is a 5- or6-membered heteroaryl ring (e.g., an optionally substituted pyridine,pyrimidine, pyrazine, pyridazine, thiophene, furan, pyrrole, imidazole,pyrazole, oxazole, isoxazole, thiazole, or isothiazole ring). In anotherembodiment, Ring C is a 5- to 7-membered cycloalkyl or heterocyclyl ring(e.g., an optionally substituted cyclohexene or dihydrofuran ring). Insome embodiments, the heterocyclyl ring contains one to twoheteroatom(s) independently selected from N, O, and S. In yet anotherembodiment, Ring C is a 6-membered aryl ring (e.g., an optionallysubstituted benzene ring). In one embodiment, Ring C is optionallysubstituted with one or more R¹², wherein R¹² is defined hereinelsewhere. In specific embodiments, R⁹ is hydrogen or methyl. Inspecific embodiments, R¹² is hydrogen.

In one embodiment, B is:

wherein R⁹ and R¹² are defined herein elsewhere.

In one embodiment, B is:

wherein each R¹² is independently hydrogen, halogen, cyano, ═O, —OR¹³,—NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³,—SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, alkyl, heteroalkyl,cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or heterocyclyl;wherein each R¹³ and R¹⁴ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or heterocyclyl;or when R¹³ and R¹⁴ are both attached to one nitrogen atom, R¹³ and R¹⁴together with the nitrogen atom to which they are attached form a 3 to10 membered ring; and Ring C is a 5- or 6-membered heteroaryl ring, a 5-to 7-membered cycloalkyl or heterocyclyl ring, or a 6-membered arylring. In one embodiment, Ring C is optionally substituted with one ormore R¹², wherein R¹² is defined herein elsewhere.

In one embodiment, B is:

wherein R⁸ and R¹² are defined herein elsewhere.

In one embodiment, B is:

wherein R⁸ and R¹² are defined herein elsewhere.

In one embodiment, B is:

wherein R⁹ and R¹² are defined herein elsewhere.

In one embodiment, each R⁸ and R¹² is independently hydrogen, halo,cyano, alkyl, or alkoxyl. In one embodiment, each R⁸ and R¹² isindependently hydrogen, halo (e.g., F or Cl), cyano, (C₁-C₄)alkyl (e.g.,methyl or CF₃), or (C₁-C₄)alkoxyl (e.g., methoxyl or OCF₃). In oneembodiment, each R⁸ and R¹² is independently hydrogen or methyl. In oneembodiment, R⁸ is hydrogen or alkyl. In one embodiment, each R¹² isindependently hydrogen, halo, cyano, alkyl, or alkoxyl (e.g., —OR¹³). Inone embodiment, R⁸ is hydrogen or (C₁-C₄)alkyl (e.g., methyl or ethyl).In one embodiment, each R¹² is independently hydrogen, halo (e.g., F orCl), cyano, (C₁-C₄)alkyl (e.g., methyl or CF₃), or (C₁-C₄)alkoxyl (e.g.,methoxyl or OCF₃). In one embodiment, R⁸ is hydrogen or methyl. In oneembodiment, each R¹² is independently hydrogen or methyl. In oneembodiment, each R⁹ and R¹² is independently hydrogen, halo, cyano,alkyl, or alkoxyl. In one embodiment, each R⁹ and R¹² is independentlyhydrogen, halo (e.g., F or Cl), cyano, (C₁-C₄)alkyl (e.g., methyl orCF₃), or (C₁-C₄)alkoxyl (e.g., methoxyl or OCF₃). In one embodiment,each R⁹ and R¹² is independently hydrogen or methyl.

In one embodiment, two occurrences of R³ together with the atoms towhich they are attached form an aryl, heteroaryl, cycloalkyl, orheterocyclyl ring, including but not limited to, an optionallysubstituted phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,imidazolyl, thienyl, or thiazolyl, or a 5- or 6-membered heterocyclylring. In one embodiment, two adjacent occurrences of R³ together withthe atoms to which they are attached form an aryl or heteroaryl ring,including but not limited to, an optionally substituted phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, thienyl, or thiazolyl. Inone embodiment, R⁴ and R⁵ together with the atoms to which they areattached form an aryl, heteroaryl, cycloalkyl, or heterocyclyl ring,including but not limited to, an optionally substituted phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, thienyl, or thiazolyl, ora 5- or 6-membered heterocyclyl ring.

In one embodiment, provided herein is a compound of formula (II-A):

or a pharmaceutically acceptable salt or stereo isomer thereof, whereinY, R¹⁰, and B are defined herein elsewhere.

In one embodiment, provided herein is a compound of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR³, R¹⁰, and B are defined herein elsewhere. In specific embodiments,each R³ is independently hydrogen, methyl, ethyl, CF₃, or halo. Inspecific embodiments, R¹⁰ is hydrogen. In specific embodiments, R¹⁰ ishydrogen or methyl.

In one embodiment, B is

wherein B¹, B², R⁴, and R⁵ are defined herein elsewhere.

In one embodiment, B is a bicyclic ring system. Examples include, butare not limited to:

In one embodiment, B is a tricyclic ring system. Examples include, butare not limited to:

In one embodiment, each R¹⁰ is independently hydrogen or methyl. In oneembodiment, at least one R¹⁰ is methyl. Examples include, but are notlimited to:

In one embodiment, provided herein is a compound of formula (II-B):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinY, R¹⁰, and B are defined herein elsewhere.

In one embodiment, provided herein is a compound of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR³, R¹⁰, and B are defined herein elsewhere. In specific embodiments,each R³ is independently hydrogen, methyl, ethyl, CF3, or halo. Inspecific embodiments, R¹⁰ is hydrogen. In specific embodiments, R¹⁰ ishydrogen or methyl.

In one embodiment, B is

wherein B¹, B², R⁴, and R⁵ are defined herein elsewhere. In oneembodiment, B is a tricyclic ring system. Examples include, but are notlimited to:

In one embodiment, provided herein is a compound of formula (II-C):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinY, R¹⁰, and B are defined herein elsewhere.

In one embodiment, provided herein is a compound of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR³, R¹⁰, and B are defined herein elsewhere. In specific embodiments,each R³ is independently hydrogen, methyl, ethyl, CF3, or halo. Inspecific embodiments, R¹⁰ is hydrogen. In specific embodiments, R¹⁰ ishydrogen or methyl.

In one embodiment, B is

wherein B¹, B², R⁴, and R⁵ are defined herein elsewhere. In oneembodiment, B is a tricyclic ring system. Examples include, but are notlimited to:

In one embodiment, provided herein is a compound of formula (II-D):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinY, R¹⁰, and B are defined herein elsewhere. In one embodiment, B is atricyclic ring system. An example includes, but is not limited to:

In other embodiments, provided herein is a compound of formula (I),wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

In other embodiments, provided herein is a compound having thestructure:

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R¹ is (i) hydrogen, halo, or cyano; or (ii)(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxyl, (C₁-C₆)aminoalkyl,(C₁-C₆)heteroalkyl, (C₃-C₆)cycloalkyl, aryl, heteroaryl, heterocyclyl,amino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which isoptionally substituted with one or more R¹², wherein R¹² is definedherein.

In one embodiment, R² is (i) hydrogen; or (ii) (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)heteroalkyl, (C₃-C₆) cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹², wherein R¹² is definedherein.

In one embodiment, each R³ is independently (i) hydrogen, halo, orcyano; (ii) (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxyl,(C₁-C₆)aminoalkyl, (C₁-C₆)heteroalkyl, (C₃-C₆)cycloalkyl, aryl,heteroaryl, heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, orsulfonyl, each of which is optionally substituted with one or more R¹²;or (iii) two adjacent occurrences of R³ together with the atoms to whichthey are attached form an aryl or heteroaryl ring optionally substitutedwith one or more R¹²; wherein R¹² is defined herein.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a monocyclic or multicyclic aryl, heteroaryl, cycloalkyl,or heterocyclyl ring, each of which is optionally substituted with oneor more R¹²; wherein R¹² is defined herein.

In one embodiment, R⁶ is (i) hydrogen, halo, or cyano; or (ii)(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxyl, (C₁-C₆)aminoalkyl,(C₁-C₆)heteroalkyl, (C₃-C₆)cycloalkyl, aralkyl, heteroaralkyl, aryl,heteroaryl, heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, orsulfonyl, each of which is optionally substituted with one or more R¹²;wherein R¹² is defined herein.

In one embodiment, R⁷ is (i) hydrogen; or (ii) (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)heteroalkyl, (C₃-C₆) cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹²; wherein R¹² is definedherein.

In one embodiment, R⁸ is (i) hydrogen; or (ii) (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)heteroalkyl, (C₃-C₆) cycloalkyl, aryl,heteroaryl, heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹²; wherein R¹² is definedherein.

In one embodiment, R⁹ is (i) hydrogen, halo, or cyano; or (ii)(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxyl, (C₁-C₆)aminoalkyl,(C₁-C₆)heteroalkyl, (C₃-C₆)cycloalkyl, aralkyl, heteroaralkyl, aryl,heteroaryl, heterocyclyl, amino, amido, carbonyl, thiol, sulfinyl, orsulfonyl, each of which is optionally substituted with one or more R¹²;wherein R¹² is defined herein.

In one embodiment, each R¹⁰ is independently hydrogen, halo, or(C₁-C₆)alkyl optionally substituted with one or more R¹²; wherein R¹² isdefined herein.

In one embodiment, each R¹¹ is hydrogen or (C₁-C₆)alkyl optionallysubstituted with one or more R¹²; wherein R¹² is defined herein.

In one embodiment, each R¹² is independently (i) hydrogen, halogen,cyano, ═O, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴; or (ii)(C₁-C₁₀)alkyl optionally substituted with one or more R¹⁵, (C₁-C₁₀)heteroalkyl optionally substituted with one or more R¹⁵,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹⁵,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹⁵,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹⁵, (6 to10 membered)aryl optionally substituted with one or more R¹⁵, (5 to 10membered)heteroaryl optionally substituted with one or more R¹⁵, or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹⁵;wherein R¹³, R¹⁴, and R¹⁵ are defined herein.

In one embodiment, each occurrence of R¹⁵ is independently hydrogen,(C₁-C₆)alkyl optionally substituted with one or more R¹³,(C₃-C₆)cycloalkyl optionally substituted with one or more R¹³, halogen,cyano, ═O, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, or —S(O)₂NR¹³R¹⁴;wherein R¹³ and R¹⁴ are defined herein.

In one embodiment, each R¹³ and R¹⁴ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, (C₃-C₆)cycloalkyl, (C₇-C₁₀)aralkyl;(C₃-C₁₂)heteroaralkyl, (6 to 10 membered) aryl, (5 to 10membered)heteroaryl, or (3 to 12 membered)heterocyclyl; or when R¹³ andR¹⁴ are both attached to one nitrogen atom, R¹³ and R¹⁴ together withthe nitrogen atom to which they are attached form a 3 to 10 memberedring.

Any of the combinations of A, B, L, m, K, X, Y, Z, B¹, B², R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and Ring C, areencompassed by this disclosure and specifically provided herein.

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. Where the compound provided herein contains analkenyl or alkenylene group, the compound may exist as one geometric(i.e., cis/trans) isomer or a mixture of geometric (i.e., cis/trans)isomers.

Where structural isomers are inter-convertible, the compound may existas a single tautomer or a mixture of tautomers. This can take the formof proton tautomerism in the compound that contains, for example, animino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain, for example, an aromatic moiety. It follows thata single compound may exhibit more than one type of isomerism.

Unless otherwise specified, the term “compound” referred to herein, suchas, a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) isintended to encompass one or more of the following: a free base of thecompound or a salt thereof, a stereoisomer or a mixture of two or morestereoisomers, a solid form (e.g., a crystal form or an amorphous form)or a mixture of two or more solid forms thereof, or a solvate (e.g., ahydrate) thereof. In certain embodiments, the term “compound” referredto herein is intended to encompass a pharmaceutical acceptable form ofthe compound, including but not limited to, a free base, apharmaceutically acceptable salt, a stereoisomer or a mixture of two ormore stereoisomers, a solid form (e.g., a crystal form or an amorphousform) or a mixture of two or more solid forms, a solvate (e.g., ahydrate), or a cocrystal thereof. In one embodiment, the term “compound”referred to herein, such as, e.g., a compound of formula (I), (II-A),(II-B), (II-C), or (II-D) is intended to encompass a solvate (e.g., ahydrate) thereof.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. In someinstances, for compounds that undergo epimerization in vivo, one ofskill in the art will recognize that administration of a compound in its(R) form is equivalent to administration of the compound in its (S)form, and vice versa. Conventional techniques for thepreparation/isolation of individual enantiomers include synthesis from asuitable optically pure precursor, asymmetric synthesis from achiralstarting materials, or resolution of an enantiomeric mixture, forexample, by chiral chromatography, recrystallization, resolution,diastereomeric salt formation, or derivatization into diastereomericadducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharma. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I, andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

In one embodiment, the compounds provided herein are modulators of a PDEenzyme. In one embodiment, the compounds provided herein are inhibitorsof a PDE enzyme. In one embodiment, the compounds provided herein areinhibitors of PDE-10. In one embodiment, the compounds provided hereinare inhibitors of PDE-10A. In one embodiment, the compounds providedherein are selective inhibitors of PDE-10. In one embodiment, thecompounds provided herein are selective inhibitors of PDE-10A. In oneembodiment, the compounds provided herein are active in one or moreanimal models for a disorder provided herein elsewhere. In oneembodiment, the compounds provided herein are active in one or moreanimal models for a CNS disorder provided herein elsewhere. In oneembodiment, the compounds provided herein are active in one or moreanimal models for psychosis, schizophrenia, or antipsychotic activity,including without limitation, the conditioned avoidance response (CAR)assay, and any other animal models for psychosis, schizophrenia orantipsychotic activity that are known in the art. In one embodiment, thecompounds provided herein are active in one or more animal models forpsychosis, schizophrenia, or antipsychotic activity, including but notlimited to, conditioned avoidance response (CAR), pre-pulse inhibition(PPI), PCP-induced hyperlocomotion, and other animal models providedherein elsewhere. In one embodiment, compounds that are active in invitro assays (e.g., PDE-10A inhibition) or in vivo models for psychosis,schizophrenia or antipsychotic activity (e.g., CAR) are furtheroptimized to improve the potency in in vitro and in vivo assays anddrug-like properties such as, e.g., solubility and lipophilicity. In oneembodiment, the compounds provided herein are useful for treating,preventing, or ameliorating one or more symptoms of schizophrenia,including, positive, negative, and cognitive symptoms. In oneembodiment, the compounds provided herein induce fewer side effects,such as weight gain, in a subject treated with the compound. In oneembodiment, the compounds provided herein induce fewer side effects,such as extrapyramidal side effects, in a subject treated with thecompound. In one embodiment, the compounds provided herein are active inone or more animal models for obesity, undesirable weight retention orweight gain, metabolic syndrome, diabetes, non-insulin dependentdiabetes, impaired glucose tolerance, or hyperglycemia, includingwithout limitation, in vivo glucose tolerance test (GTT), diet-inducedobesity model, obesity food intake model, and any other animal modelsknown in the art or provided herein elsewhere. In one embodiment,compounds that are active in in vitro assays (e.g., PDE-10A inhibition)or in vivo models for obesity, undesirable weight retention or weightgain, metabolic syndrome, diabetes, non-insulin dependent diabetes,impaired glucose tolerance, or hyperglycemia are further optimized toimprove the potency in in vitro and in vivo assays and drug-likeproperties such as, e.g., solubility and lipophilicity.

C. Synthetic Schemes

Schemes below provide exemplary synthetic methods for the preparation ofthe compounds provided herein. One of ordinary skills in the art willunderstand that similar methods may be employed to prepare the compoundsprovided herein. In other words, one of ordinary skills in the art willrecognize that suitable adjustments to reagents, protecting groups,reaction conditions, and reaction sequences may be employed to prepare adesired embodiment. The reactions may be scaled upwards or downwards tosuit the amount of material to be prepared.

In one embodiment, the compound of formula (I) may be prepared followingSchemes 1-4, using suitable starting materials known in the art and/oravailable from a commercial source. In one embodiment, the startingmaterials of Schemes 1-4 may be prepared from commercially availablecompounds using procedures and conditions known in the art. Exemplaryprocedures and conditions are provided herein elsewhere.

In one embodiment, a suitable triphenylphosphine halide (e.g., asubstituted methyltriphenylphosphine chloride or bromide) is reactedwith a suitable aldehyde or ketone in the presence of a base to render asubstituted ethylene (Scheme 1), which may be further reduced (e.g., byhydrogenation) to render a substituted ethane compound as shown inScheme 1. In one embodiment, A or B may be further converted into othersuitable embodiments of A or B (e.g., transformation of substitutiongroups) using procedures and conditions known in the art.

In one embodiment, a suitable A-CH₃ is reacted with a suitable aldehydein the presence of acid (e.g., acetic acid, zinc chloride, heating) torender a substituted ethylene (Scheme 2), which may be further reduced(e.g., by hydrogenation) to render a substituted ethane compound asshown in Scheme 2. In one embodiment, A or B may be further convertedinto other suitable embodiments of A or B (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In another embodiment, a suitable A-CH₃ is reacted with a suitablealdehyde in the presence of acid (e.g., acetic acid, heating) to rendera substituted hydroxylethylene compound (Scheme 3), which is convertedto the corresponding chloride (e.g., using SOCl₂) and reduced (e.g.,using Pd on Carbon) to render a substituted ethane compound as shown inScheme 3. In one embodiment, A or B may be further converted into othersuitable embodiments of A or B (e.g., transformation of substitutiongroups) using procedures and conditions known in the art.

In one embodiment, a suitable substituted diaminoaryl or substituteddiaminoheteroaryl is reacted with a suitable substituted propionic acidunder amide coupling conditions to yield the corresponding amide (Scheme4), which is cyclized under acidic condition (e.g., acetic acid) torender a substituted ethyl-imidazole compound as shown in Scheme 4. Inone embodiment, the diaminoaryl or diaminoheteroaryl compound issubstituted with one or more R, a suitable substituent, which may be thesame or different, and two adjacent occurrences of R may together withthe atoms to which they are attached form a ring (e.g., aryl,heteroaryl, heterocyclyl, or cycloalkyl ring, which is optionallysubstituted as defined herein elsewhere). In one embodiment, Ar or R maybe further converted into other suitable embodiments of Ar or R. (e.g.,transformation of substitution groups) using procedures and conditionsknown in the art. In one embodiment, the imidazole ring may be furtheralkylated to render an N-substituted imidazole compound.

In other embodiments, the compounds provided herein may be preparedusing the general procedures described herein below. In one embodiment,the compounds provided herein may be prepared using General Procedure A.In one embodiment, the compounds provided herein may be prepared usingGeneral Procedure B. In one embodiment, the compounds provided hereinmay be prepared using General Procedure C. In one embodiment, thecompounds provided herein may be prepared using General Procedure D. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure E. In one embodiment, the compounds provided hereinmay be prepared using General Procedure F. In one embodiment, thecompounds provided herein may be prepared using General Procedure G. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure H. In one embodiment, the compounds provided hereinmay be prepared using General Procedure I. In one embodiment, thecompounds provided herein may be prepared using General Procedure J. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure K. In one embodiment, the compounds provided hereinmay be prepared using General Procedure L. In one embodiment, thecompounds provided herein may be prepared using General Procedure M. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure N. In one embodiment, the compounds provided hereinmay be prepared using General Procedure O. In one embodiment, thecompounds provided herein may be prepared using General Procedure P. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure Q. In one embodiment, the compounds provided hereinmay be prepared using General Procedure R. In one embodiment, thecompounds provided herein may be prepared using General Procedure S. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure T. In one embodiment, the compounds provided hereinmay be prepared using General Procedure U. In one embodiment, thecompounds provided herein may be prepared using General Procedure V. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure W. In one embodiment, the compounds provided hereinmay be prepared using General Procedure X. In one embodiment, thecompounds provided herein may be prepared using General Procedure Y. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure Z.

In certain embodiments, the compounds provided herein are prepared as amixture of two or more stereoisomers or diastereoisomers. In oneembodiment, the stereoisomers or diastereoisomers are separated usingtechniques known to those skilled in the art, including but not limitedto, chiral column chromatography and chiral resolution by forming a saltwith a suitable chiral counterion. In certain embodiments, the compoundsprovided herein are prepared following one or more stereoselectivereaction(s). In some embodiment, the compounds provided herein areprepared as a substantially pure stereoisomer.

D. Methods of Use

1. Modulation of PDE Enzyme Activity

In one embodiment, provided herein is a method of binding a compoundprovided herein to a PDE enzyme, such as, PDE-10, in one embodiment,PDE-10A. The method comprises contacting the PDE enzyme with a compoundprovided herein. In one embodiment, the binding to PDE enzyme isassessed using an in vitro binding assay, such as those known in theart.

In one embodiment, provided herein is a method of modulating (e.g.,inhibiting or augmenting) the activity of a PDE enzyme, such as, PDE-10,in one embodiment, PDE-10A. In one embodiment, provided herein is amethod of inhibiting the activity of a PDE enzyme, such as, PDE-10, inone embodiment, PDE-10A. In one embodiment, the method comprisescontacting a PDE enzyme, such as PDE-10A, with a compound providedherein, in vitro or in vivo. In one embodiment, the PDE enzyme, such asPDE-10A, is contacted by a compound provided herein by administering toa subject a therapeutically effective amount of the compound providedherein, or a pharmaceutically acceptable salt or stereoisomer thereof.The subject may be a human. In one embodiment, the PDE enzyme is PDE-10.In one embodiment, the PDE enzyme is PDE-10A.

In other embodiments, the compound provided herein inhibits the activityof a PDE enzyme, such as PDE-10A. Inhibition of PDE activity may bemeasured using assays known in the art. In some embodiments, theactivity of the PDE enzyme is inhibited or reduced by about 1%, about5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, about 95%, about 99% or more than about99%, as compared with activity without contacting the PDE enzyme with acompound provided herein (e.g., vehicle condition). In one embodiment,the inhibition of enzyme activity is dose dependent. Exemplary assaymethods include, but are not limited to, in vitro binding assays and invitro functional assays. In one embodiment, the functional assayutilizes an appropriate cell-line expressing a desired PDE enzyme, suchas PDE-10A. In one embodiment, the functional assay utilizes a PDEenzyme purified following expression using an appropriate recombinantsystem. In one embodiment, inhibition of PDE enzyme activity may beassessed using a fluorescent assay, e.g., utilizing aFluorescein-labeled cAMP/cGMP substrate. In one embodiment, thefunctional assay utilizes synaptosomes isolated from brain tissue of anappropriate organism. In one embodiment, the assay is carried out invivo and involves treatment of a test subject (e.g., a rodent) with acompound provided herein. In one embodiment, a test subject is treatedwith a reference compound or vehicle, as positive or negative controls.In one embodiment, the assay is followed by isolation of brain tissueand ex vivo analysis of substrate concentration (e.g., cAMP or cGMP) inthe brain tissue. In one embodiment, the assay is followed by isolationof brain microdialysates and ex vivo analysis of substrate concentration(e.g., cAMP or cGMP) in the microdialysates.

In certain embodiments, provided herein are methods of inhibiting theactivity of a PDE enzyme, e.g., PDE-10A, in a subject (e.g., human)comprising administering to the subject an effective amount of acompound provided herein. In some embodiments, the activity of PDEenzyme is inhibited by about 1%, about 5%, about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, about 99%, or more than about 99%, when measured using anassay described herein elsewhere.

In one embodiment, provided herein is a method of inhibiting a PDEenzyme to increase the concentration of a cyclic nucleotide substrate.In one embodiment, the method includes contacting the cell with acompound provided herein. In one embodiment, the cell is a brain cell,such as a medium spiny neuron. In one embodiment, the enzyme inhibitionoccurs in vitro. In one embodiment, the enzyme inhibition occurs invivo. Thus, in certain embodiments, provided herein are methods ofincreasing the level of a cyclic nucleotide substrate (e.g., cAMP orcGMP) comprising administering to a subject (e.g., human) an effectiveamount of a compound provided herein.

Inhibition of PDE enzyme can be shown, for example, by performingvarious in vitro functional assays utilizing a cell type which expressesa certain type of PDE enzyme, such as PDE-10A, together with anappropriate labeled cyclic nucleotide substrate. In some embodiments,the compounds provided herein inhibit the PDE enzyme in a dose-dependentmanner, with an EC₅₀ of, for example, between about 0.1 nM and about 10nM, between about 1 nM and about 1 μM, between about 1 nM and about 500nM, and between about 1 nM and about 100 nM, in a functional PDEinhibition assay, such as those described herein. In one embodiment, theEC₅₀ is less than about 0.01 nM, less than about 0.1 nM, less than about1 nM, less than about 3 nM, less than about 10 nM, less than about 30nM, less than about 100 nM, less than about 300 nM, less than about 1000nM, less than about 3000 nM, or less than about 10000 nM. In oneembodiment, the EC₅₀ is about 0.01 nM, about 0.1 nM, about 1 nM, about 3nM, about 10 nM, about 30 nM, about 100 nM, about 300 nM, about 1000 nM,about 3000 nM, or about 10000 nM.

2. Treatment, Prevention, and/or Management of Disorders

In one embodiment, provided herein is a method for the treatment,prevention, and/or management of various disorders, including a disorderof the central nervous system, comprising administering a compound or acomposition provided herein. In one embodiment, provided herein is amethod for the treatment, prevention, and/or amelioration of one or moresymptoms of a disorder (e.g., a CNS disorder), comprising administeringa compound or a composition provided herein. In one embodiment, thedisorders provided herein include, but are not limited to,schizophrenia, psychosis, cognitive disorders, mood disorders,depression, attention deficit disorders, and neurodegenerative diseases.In one embodiment, the disorders include, but are not limited to,neurological disorder, schizophrenia, schizophrenia-related disorders,schizophrenia spectrum disorder, acute schizophrenia, chronicschizophrenia, NOS schizophrenia, schizoaffective disorder,schizophreniform disorder, paraphrenia, paranoid personality disorder,schizoid personality disorder, schizotypal personality disorder,delusional disorder, psychosis, disease having a psychosis component,psychotic disorder, brief psychotic disorder, Alzheimer's psychosis,Parkinson's psychosis, shared psychotic disorder, substance-inducedpsychotic disorder (e.g., cocaine, alcohol, amphetamine), psychoticdisorder due to a general medical condition, psychoaffective disorder,aggression, delirium, excitative psychosis, Tourette's syndrome, manicdisorder, organic psychosis, NOS psychosis, convulsion, seizure,agitation, posttraumatic stress disorder, behavior disorder,neurodegenerative disease, Huntington's disease, Alzheimer's disease,Parkinson's disease, dyskinesia, dementia, mood disorder, bipolardisorder, anxiety, depression, major depressive disorder, unipolardepression, treatment resistant depression, dysthymia, affectivedisorder, seasonal affective disorder, obsessive-compulsive disorder,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), vertigo, pain, neuropathic pain, sensitizationaccompanying neuropathic pain, inflammatory pain, fibromyalgia,migraine, cognitive impairment, cognitive impairment associated withschizophrenia, cognitive deficit in Alzheimer's disease, cognitivedeficit in Parkinson's disease, movement disorder, restless leg syndrome(RLS), multiple sclerosis, sleep disorder, substance abuse or dependency(e.g., nicotine, cocaine), addiction, eating disorder, autism, obesity,undesirable weight retention or weight gain, metabolic syndrome,diabetes, non-insulin dependent diabetes, impaired glucose tolerance,and hyperglycemia. In one embodiment, the disorder provided herein is adisorder known in the art that affects the central nervous system (i.e.,a CNS disorder).

In one embodiment, provided herein is a method of administering acompound provided herein in a disease model that is known in the art. Inone embodiment, the disease model is an animal model. In one embodiment,provided herein is a method of administering the compound providedherein in an animal model that is predictive of efficacy in thetreatment of certain diseases in a human. The method comprisesadministering a compound provided herein in a subject. In oneembodiment, the method comprises administering to a subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt or stereoisomer thereof. In oneembodiment, the method comprises treatment of a test subject (e.g., amice or rat) with a compound provided herein. In one embodiment, themethod comprises treatment of a test subject (e.g., a mice or rat) witha compound provided herein as well as a reference compound. In oneembodiment, the in vivo activity of the compound provided herein is dosedependent. In one embodiment, without being limited to a particulartheory, the method provided herein comprises administering an effectiveamount of a compound provided herein to inhibit PDE-10 activity in asubject. In one embodiment, without being limited to a particulartheory, the method provided herein comprises administering an effectiveamount of a compound provided herein to inhibit PDE-10A activity in asubject.

In one embodiment, the compounds provided herein are active in one ormore animal models of schizophrenia or psychosis, such as conditionedavoidance responding (CAR), auditory gating (e.g., amphetamine-induceddeficit in auditory gating), phencyclidine (PCP)-inducedhyperlocomotion, stimulant-induced hyperlocomotion/hyperactivity,PCP-induced hyperactivity, and amphetamine-induced hyperactivity. In oneembodiment, the compounds provided herein inhibit exploratory locomotoractivity and/or hyperactivity caused by a dopamine releasing agent, suchas amphetamine, and/or a NMDA receptor antagonist, such as phencyclidine(PCP). In one embodiment, the compounds provided herein inhibitconditioned avoidance responding. In one embodiment, the compoundsprovided herein are active in pre-pulse inhibition (PPI) of acousticstartle response model. In one embodiment, the compounds provided hereininhibit spontaneous locomotor activity. In one embodiment, the compoundsprovided herein improve cognitive function in a treated subject. In oneembodiment, the compounds provided herein improve social interaction ina treated subject. In one embodiment, the compounds provided hereinimprove social cognition in a treated subject. In one embodiment, thecompounds provided herein improve executive function in a treatedsubject. In one embodiment, the compounds provided herein caused reducedParkinsonian side effects in a treated subject. In one embodiment, thecompounds provided herein produce relatively low levels of catalepsy, ascompared to other therapeutic agents. In one embodiment, the compoundsprovided herein provide a neuron-protective effect on neurons, such asmedium spiny neurons, in a treated subject. In one embodiment, thecompounds provided herein are active in a striatal quinolinic acidlesion model for Huntington's disease. In one embodiment, the compoundsprovided herein are active in dizocilpine-induced hyperactivity andstereotyped sniffing model for psychosis. In one embodiment, thecompounds provided herein inhibit apomorphine-induced climbing. In oneembodiment, the compounds provided herein inhibit N-methyl-D-aspartateantagonist-induced deficits in pre-pulse inhibition of acoustic startleresponse. In one embodiment, the compounds provided herein improvebaseline sensory gating. In one embodiment, the compounds providedherein increase sociality in a social approach/social avoidance assay.In one embodiment, the compounds provided herein enhance social odorrecognition. In one embodiment, the compounds provided herein improvenovel object recognition. In one embodiment, the compounds providedherein are active in a disease model for a disorder provided hereinelsewhere, which is known in the art. See, e.g., Grauer et al.,Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of thePositive, Cognitive, and Negative Symptoms of Schizophrenia, Journal ofPharmacology and Experimental Therapeutics, 2009, 331(2), 574-90;Threlfell et al., Inhibition of Phosphodiesterase 10A Increases theResponsiveness of Striatal Projection Neurons to Cortical Stimulation,Journal of Pharmacology and Experimental Therapeutics, 2009, 328(3),785-95; Schmidt et al., Preclinical Characterization of SelectivePhosphodiesterase 10A Inhibitors: A New Therapeutic Approach to theTreatment of Schizophrenia, Journal of Pharmacology and ExperimentalTherapeutics, 2008, 325(2), 681-90.

In one embodiment, provided herein is a method of treating, preventing,and/or managing various disorders, including, but not limited to, adisorder of the central nervous system. In one embodiment, the methodcomprises administering to a subject (e.g., human) a therapeutically orprophylactically effective amount of a composition or a compoundprovided herein. In one embodiment, the subject is a human. In oneembodiment, the subject is an animal. In one embodiment, the compoundsprovided herein are highly brain penetrable in the subject. In certainembodiments, the efficacious concentration of the compounds providedherein is less than 10 nM, less than 100 nM, less than 1 μM, less than10 μM, less than 100 μM, or less than 1 mM. In one embodiment, thecompound's activity may be assessed in various art-recognized animalmodels as described herein elsewhere or known in the literature.

In one embodiment, without being limited by a particular theory, thetreatment, prevention, and/or management is done by administering acompound provided herein that has shown in vivo efficacy in an animalmodel predictive of efficacy in humans.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to a CNS disorder, a neurologicaldisorder, schizophrenia, a schizophrenia-related disorder, schizophreniaspectrum disorder, acute schizophrenia, chronic schizophrenia, NOSschizophrenia, schizoaffective disorder, schizophreniform disorder,paraphrenia, paranoid personality disorder, schizoid personalitydisorder, schizotypal personality disorder, delusional disorder,psychosis, a disease having a psychosis component, psychotic disorder,brief psychotic disorder, Alzheimer's psychosis, Parkinson's psychosis,shared psychotic disorder, substance-induced psychotic disorder (e.g.,cocaine, alcohol, amphetamine), psychotic disorder due to a generalmedical condition, psychoaffective disorder, aggression, delirium,excitative psychosis, Tourette's syndrome, manic disorder, organicpsychosis, NOS psychosis, convulsion, seizure, agitation, posttraumaticstress disorder, behavior disorder, neurodegenerative disease,Huntington's disease, Alzheimer's disease, Parkinson's disease,dyskinesias, dementia, mood disorder, bipolar disorder, anxiety,depression, major depressive disorder, unipolar depression, treatmentresistant depression, dysthymia, affective disorder, seasonal affectivedisorder, obsessive-compulsive disorder, attention deficit disorder(ADD), attention deficit hyperactivity disorder (ADHD), vertigo, pain,neuropathic pain, sensitization accompanying neuropathic pain,inflammatory pain, fibromyalgia, migraine, cognitive impairment,cognitive impairment associated with schizophrenia, cognitive deficit inAlzheimer's disease, cognitive deficit in Parkinson's disease, movementdisorder, restless leg syndrome (RLS), multiple sclerosis, sleepdisorder, substance abuse or dependency (e.g., nicotine, cocaine),addiction, eating disorder, autism, obesity, undesirable weightretention or weight gain, metabolic syndrome, diabetes, non-insulindependent diabetes, impaired glucose tolerance, or hyperglycemia,comprising administering to a subject an effective amount of a compoundprovided herein. In one embodiment, provided herein is a method oftreating, preventing, and/or managing a disorder selected fromschizophrenia, cognitive impairment associated with schizophrenia,cognitive impairment, psychosis, depression, and Huntington's disease,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurological disorder as provided herein elsewhere,such as schizophrenia, psychosis, cognitive impairment, depression,Alzheimer's disease, Parkinson's disease, and attention deficithyperactivity disorder (ADHD), and the like, comprising administering toa subject an effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing schizophrenia or a schizophrenia-related disorder,including but not limited to schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoaffectivedisorder, schizophreniform disorder, paraphrenia, paranoid personalitydisorder, schizoid personality disorder, schizotypal personalitydisorder, delusional disorder, and psychosis, comprising administeringto a subject an effective amount of a compound provided herein. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more positive symptoms of schizophrenia. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more negative symptoms of schizophrenia. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more cognitive symptoms of schizophrenia.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disease having a psychosis component, including butnot limited to psychotic disorder, brief psychotic disorder, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder,substance-induced psychotic disorder (e.g., cocaine, alcohol, oramphetamine), psychotic disorder due to a general medical condition,psychoaffective disorder, aggression, delirium, excitative psychosis,Tourette's syndrome, manic disorder, organic psychosis, and NOSpsychosis, comprising administering to a subject an effective amount ofa compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing cognitive impairment, including but not limited tocognitive impairment associated with schizophrenia, cognitive deficit inAlzheimer's disease, cognitive deficit in Parkinson's disease,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing mood disorder, bipolar disorder, anxiety, depression,major depressive disorder, unipolar depression, treatment resistantdepression, dysthymia, affective disorder, seasonal affective disorder,or obsessive-compulsive disorder, comprising administering to a subjectan effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing attention deficit disorder (ADD) or attention deficithyperactivity disorder (ADHD), comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurodegenerative disease, including but not limitedto Huntington's disease, Alzheimer's disease, and Parkinson's disease,comprising administering to a subject an effective amount of a compoundprovided herein. In one embodiment, provided herein is a method oftreating, preventing, and/or managing Huntington's disease, comprisingadministering to a subject an effective amount of a compound providedherein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing agitation, posttraumatic stress disorder, or behaviordisorder, comprising administering to a subject an effective amount of acompound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing dementia, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing vertigo, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing pain, neuropathic pain, sensitization accompanyingneuropathic pain, inflammatory pain, migraine or fibromyalgia,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing movement disorder or restless leg syndrome (RLS),comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing multiple sclerosis, sleep disorder, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, orautism, comprising administering to a subject an effective amount of acompound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to cognitive impairments, such asthose associated with Alzheimer's disease, Parkinson's disease,schizophrenia, and attention deficit hyperactivity disorder (ADHD), andthe like, comprising administering to a subject an effective amount of acompound provided herein. For example, without being limited by aparticular theory, the compounds provided herein may have pro-cognitiveeffects, such as passive avoidance, novel object recognition, socialrecognition, and attention-set shifting. Further, without being limitedby a particular theory, the compounds provided herein may improve socialmemory, increase the acquisition of an environment, and reversescopolamine-induced deficits. The compounds provided herein may alsoreverse scopolamine-induced deficits in a passive avoidance memory test.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a psychotic disorder or psychotic condition, includingbut not limited to, schizophrenia, delusional disorders and drug inducedpsychosis, comprising administering to a subject an effective amount ofa compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing an anxiety disorder, including but not limited to, panicand obsessive-compulsive disorder, comprising administering to a subjectan effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a movement disorder, including but not limited to,Parkinson's disease and Huntington's disease, comprising administeringto a subject an effective amount of a compound provided herein.

In one embodiment, the psychotic disorders provided herein that can betreated, prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,schizophrenia, e.g., of the paranoid, disorganized, catatonic,undifferentiated, and/or residual type; schizophreniform disorder;schizoaffective disorder, e.g., of the delusional and/or depressivetype; delusional disorder; substance-induced psychotic disorder, e.g.,psychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, and/or phencyclidine; personalitydisorder of the paranoid type; and personality disorder of the schizoidtype.

In one embodiment, the movement disorders provided herein that can betreated, prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,Huntington's disease, dyskinesia associated with dopamine agonisttherapy, Parkinson's disease, restless leg syndrome, and essentialtremor.

In one embodiment, other disorders provided herein that can be treated,prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,obsessive-compulsive disorder, Tourette's syndrome, and tic disorders.

In one embodiment, provided herein is a method of treating, preventing,and/or managing an anxiety disorder, including but not limited to, panicdisorder, agoraphobia, specific phobia, social phobia,obsessive-compulsive disorder, post-traumatic stress disorder, acutestress disorder, and generalized anxiety disorder, comprisingadministering to a subject an effective amount of a compound providedherein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a drug addiction, including but not limited to, analcohol, amphetamine, cocaine, and/or opiate addiction, comprisingadministering to a subject an effective amount of a compound providedherein. In one embodiment, the drug addiction provided herein representsan abnormal desire for a drug and is generally characterized bymotivational disturbances such a compulsion to take the desired drug andepisodes of intense drug craving.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder comprising a symptom of deficiency inattention and/or cognition, comprising administering to a subject aneffective amount of a compound provided herein. In one embodiment,deficiency in attention and/or cognition provided herein may represent asubnormal functioning in one or more cognitive aspects, such as, e.g.,memory, intellect, learning ability, and/or logic ability, in aparticular subject relative to other subjects within the same generalpopulation and/or age group. In one embodiment, deficiency in attentionand/or cognition provided herein may represent a reduction in aparticular sub-population's functioning in one or more cognitiveaspects, such as, e.g., in age-related cognitive decline.

In one embodiment, the disorders comprising a symptom of deficiency inattention and/or cognition provided herein that can be treated,prevented, and/or managed with a compound or a pharmaceuticalcomposition provided herein, include, but are not limited to, dementia,e.g., dementia in Alzheimer's disease, multi-infarct dementia, alcoholicdementia, drug-related dementia, dementia associated with intracranialtumors, dementia associated with cerebral trauma, dementia associatedwith Huntington's disease, dementia associated with Parkinson's disease,or AIDS-related dementia; delirium; amnestic disorder; post-traumaticstress disorder; mental retardation; learning disorder, e.g., readingdisorder, mathematics disorder, or a disorder of written expression;attention-deficit/hyperactivity disorder; and age-related cognitivedecline.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a mood disorder or a mood episode, comprisingadministering to a subject an effective amount of a compound providedherein. In one embodiment, the mood disorders or mood episodes providedherein that can be treated, prevented, and/or managed with a compound ora pharmaceutical composition provided herein include, but are notlimited to, major depressive episode of the mild, moderate or severetype; a manic or mixed mood episode; a hypomanic mood episode; adepressive episode with atypical features; a depressive episode withmelancholic features; a depressive episode with catatonic features; amood episode with postpartum onset; post-stroke depression; majordepressive disorder; treatment resistant depression; dysthymic disorder;minor depressive disorder; premenstrual dysphoric disorder;post-psychotic depressive disorder of schizophrenia; a major depressivedisorder superimposed on a psychotic disorder such as delusionaldisorder or schizophrenia; a bipolar disorder, e.g., bipolar I disorder,bipolar II disorder, and cyclothymic disorder.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurodegenerative disorder or neurodegenerativecondition, comprising administering to a subject an effective amount ofa compound provided herein. In one embodiment, the neurodegenerativedisorder or neurodegenerative condition provided herein that can betreated, prevented, and/or managed with a compound or a pharmaceuticalcomposition provided herein represents a disorder or condition that iscaused by the dysfunction and/or death of neurons in the central nervoussystem. The treatment of these disorders and conditions can befacilitated by administration of an agent which prevents the dysfunctionor death of neurons at risk and/or enhances the function of damaged orhealthy neurons to compensate for the loss of function caused by thedysfunction or death of at-risk neurons. In one embodiment, theneurodegenerative disorders or neurodegenerative conditions providedherein that can be treated, prevented, and/or managed with a compound ora pharmaceutical composition provided herein include, but are notlimited to, Parkinson's disease; Huntington's disease; dementia, e.g.,Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal dementia; neurodegeneration associated with cerebraltrauma; neurodegeneration associated with stroke; neurodegenerationassociated with cerebral infarct; hypoglycemia-inducedneurodegeneration; neurodegeneration associated with neurotoxinpoisoning; and multi-system atrophy. In one embodiment, theneurodegenerative disorders or neurodegenerative conditions providedherein comprise neurodegeneration of striatal medium spiny neurons in asubject. In one embodiment, the neurodegenerative disorder orneurodegenerative condition is Huntington's disease.

In one embodiment, provided herein is a method of treating, preventing,and/or managing psychotic disorder, delusional disorder, drug inducedpsychosis, anxiety disorder, movement disorder, mood disorder,neurodegenerative disorder, or drug addiction, comprising administeringto a subject an effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurologic disorder, including but not limited to,dementia, Alzheimer's disease, multi-infarct dementia, alcoholicdementia, drug-related dementia, dementia associated with intracranialtumors, dementia associated with cerebral trauma, dementia associatedwith Huntington's disease, dementia associated with Parkinson's disease,AIDS-related dementia, delirium, amnestic disorder, post-traumaticstress disorder, mental retardation, learning disorder, readingdisorder, mathematics disorder, disorder of written expression,attention-deficit-hyperactivity disorder, age-related cognitive decline,major depressive episode of the mild, moderate or severe type, manic ormixed mood episode, hypomanic mood episode, depressive episode withatypical features, depressive episode with melancholic features,depressive episode with catatonic features, mood episode with postpartumonset, post-stroke depression, major depressive disorder, dysthymicdisorder, minor depressive disorder, premenstrual dysphoric disorder,post-psychotic depressive disorder of schizophrenia, a major depressivedisorder superimposed on a psychotic disorder comprising a delusionaldisorder or schizophrenia, bipolar disorder, bipolar I disorder, bipolarII disorder, cyclothytnic disorder, Parkinson's disease, Huntington'sdisease, dementia, Alzheimer's disease, multi-infarct dementia,AIDS-related dementia, Fronto temperal dementia, neurodegenerationassociated with cerebral trauma, neurodegeneration associated withstroke, neurodegeneration associated with cerebral infarct,hypoglycemia-induced neurodegeneration, neurodegeneration associatedwith neurotoxin poisoning, multi-system atrophy, schizophrenia of aparanoid, disorganized, catatonic, undifferentiated or residual type,schizophreniform disorder; schizoaffective disorder of the delusionaltype or the depressive type, delusional disorder, substance-inducedpsychotic disorder, psychosis induced by alcohol, amphetamine, cannabis,cocaine, hallucinogens, inhalants, opioids, or phencyclidine,personality disorder of the paranoid type, and personality disorder ofthe schizoid type, comprising administering to a subject an effectiveamount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurologic disorder, including but not limited to,psychotic disorders, delusional disorders, drug induced psychosis,anxiety disorders, movement disorders, mood disorders, neurodegenerativedisorders, and drug addiction, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing substance abuse, comprising administering to a subjectan effective amount of a compound provided herein. For example, withoutbeing limited by a particular theory, the compounds provided herein mayalter methamphetamine self-administration in rats, and therefore thecompounds provided herein may ameliorate the craving for addictivedrugs.

In one embodiment, provided herein is a method of using the compoundsprovided herein as psycho-stimulants, which may lack the abuseliabilities generally associated with other classes ofpsycho-stimulants.

In one embodiment, provided herein is a method of treating, preventing,and/or managing movement disorders, such as Parkinson's disease, L-dopainduced dyskineasias, peak dose dyskinesas, restless leg syndrome (RLS),and Huntington's disease, comprising administering to a subject aneffective amount of a compound provided herein.

In some embodiments, the compounds provided herein are active in atleast one model, which can be used to measure the activity of thecompounds and estimate their efficacy in treating a CNS disorder. Forexample, the compounds provided herein are active in at least one modelfor schizophrenia, such as, e.g., conditioned avoidance responding,amphetamine-induced deficit in auditory gating, phencyclidine-inducedhyperlocomotion or hyperactivity, and amphetamine-induced hyperactivitymodels. The compounds are active when they induce a desired response inthe animal (e.g., mice) by a statistically significant amount comparedto vehicle-treated animals.

In other embodiments, provided herein is a method of effecting atherapeutic effect as described herein elsewhere. The method comprisesadministering to a subject (e.g., a mammal) a therapeutically effectiveamount of a compound or a composition provided herein. The particulartherapeutic effects may be measured using any model system known in theart and described herein, such as those involving an animal model of adisease.

In some embodiments, the neurological disorder provided herein is:depression (e.g., major depressive disorder, bipolar disorder, unipolardisorder, treatment resistant depression, dysthymia, and seasonalaffective disorder); cognitive deficits; fibromyalgia; pain (e.g.,neuropathic pain); sleep related disorders (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; attentiondeficit disorder (ADD); attention deficit hyperactivity disorder (ADHD);restless leg syndrome; schizophrenia; anxieties (e.g., general anxietydisorder, social anxiety disorder, panic disorder); obsessive compulsivedisorder; posttraumatic stress disorder; seasonal affective disorder(SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis); manicconditions; dysthymic disorder; cyclothymic disorder; obesity; andsubstance abuse or dependency (e.g., cocaine addiction, nicotineaddiction). In another embodiment, the compounds provided herein areuseful to treat, prevent, and/or manage two or moreconditions/disorders, which are co-morbid, such as psychosis anddepression.

Neurological disorders may also include cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, lowering ofattention, speech disorders, autism, and hyperkinetic syndrome.

Neuropathic pain includes, without limitation, post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds, and/or compositionsprovided herein include, but are not limited to: obesity, overweight,metabolic syndrome, diabetes, non-insulin dependent diabetes, impairedglucose tolerance, and hyperglycemia.

In one embodiment, the neurological disorder is excessive daytimesleepiness. In another embodiment, the neurological disorder iscognitive impairment. In another embodiment, the neurological disorderis mood disorders. In another embodiment, the neurological disorder ismovement disorders. In another embodiment, the neurological disorder isschizophrenia. In another embodiment, the neurological disorder isattention disorders. In another embodiment, the neurological disorder isanxiety disorder. In another embodiment, the neurological disorder isseizure. In another embodiment, the neurological disorder is psychosis.In another embodiment, the neurological disorder is vertigo. In anotherembodiment, the neurological disorder is pain. In another embodiment,the neurological disorder is neuropathic pain. In another embodiment,the neuropathic pain is diabetic neuropathy.

In one embodiment, the neurological disorder is a neurodegenerativedisease. In one embodiment, the neurodegenerative disease is Parkinson'sdisease. In another embodiment, the neurodegenerative disorder isAlzheimer's disease.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a central nervous disorder, without causing addiction to saidcompounds.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Exemplary routesof administration include oral, transdermal, and mucosal. Suitabledosage forms for such routes include, but are not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose. An exemplary transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound provided herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. The dosage maybe formulated as a single or multiple unit dosage formulation. In oneembodiment, the compound is given in single or divided doses per day.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein (e.g., administered to asubject need thereof). In certain embodiments, the second active agentis an antipsychotic agent. In certain embodiments, the second activeagent is an atypical antipsychotic agent. In certain embodiments, thesecond active agent is an agent that is useful for the treatment ofAlzheimer's disease. In certain embodiments, the second active agent isa cholinesterase inhibitor. In certain embodiments, the second activeagent is an antidepressant agent. In certain embodiments, the secondactive agent is selected from an SSRI, SNRI, and tricyclicantidepressants. In certain embodiments, the second active agent islurasidone, olanzapine, risperidone, aripiprazole, amisulpride,asenapine, blonanserin, clozapine, clotiapine, illoperidone,mosapratnine, paliperidone, quetiapine, remoxipride, sertindole,sulpiride, ziprasidone, zotepine, pimavanserin, loxapine, donepezil,rivastigmine, memantine, galantamine, tacrine, amphetamine,methylphenidate, atomoxetine, modafinil, sertraline, fluoxetine,venlafaxine, duloxetine, or L-DOPA.

3. Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients (e.g., a secondactive agent provided herein elsewhere). Examples of optional second, oradditional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintra-arterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing, Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or disaccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising, active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients.

In other embodiments, dosage forms comprise the second activeingredient. The specific amount of the second active agent will dependon the specific agent used, the diseases or disorders being treated ormanaged, and the amount(s) of a compound provided herein, and anyoptional additional active agents concurrently administered to thepatient.

(a) Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or non-aqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, and optional excipients, such as anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

(b) Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

(c) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

(d) Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4. Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

VI. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. General Procedures for Compound Synthesis

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich® Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Aldrich in Sure-Seal® bottles andused as received. All solvents may be purified using standard methodsknown to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. The reaction flasks were fittedwith rubber septa for introduction of substrates and reagents viasyringe. Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates and eluted with appropriatesolvent ratios (v/v). Reactions were assayed by TLC or liquidchromatography mass spectroscopy (LCMS), and terminated as judged by theconsumption of starting material. Visualization of the TLC plates wasdone with UV light (254 wavelength) or with an appropriate TLCvisualizing solvent, such as basic aqueous KMnO₄ solution activated withheat. Flash column chromatography (see, e.g., Still et al., J. Org.Chem., 43: 2923 (1978)) was performed using silica gel 60 or variousmedium-pressure liquid chromatography (MPLC) systems (such as Biotage®or ISCO® separation systems).

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, elemental microanalysis, and melting point. Protonnuclear magnetic resonance (¹H NMR) spectra were determined using a NMRspectrometer operating at a certain field strength. Chemical shifts arereported in parts per million (ppm, δ) downfield from an internalstandard, such as tetramethylsilane (TMS). Alternatively, ¹H NMR spectrawere referenced to signals from residual protons in deuterated solventsas follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; br, broadened; and m, multiplet. Coupling constants aregiven in Hertz (Hz). Mass spectra (MS) data were obtained using a massspectrometer with APCI or ESI ionization.

a. 1-Amino-2,5-dimethylpyrazin-1-ium-2,4,6-trimethylbenzenesulfonate

A solution of 2,5-dimethylpyrazine (3.24 g, 30.0 mmol) indichloromethane (DCM) (30 mL) was cooled to 0° C. A solution ofO-(mesitylsulfonyl)hydroxylamine (12.9 g, 60.0 mmol) in DCM (30 mL) wasadded. The mixture was stirred at 0° C. for 1 h. Then diethyl ether(Et₂O) (150 mL) was added. The precipitate was filtered and collected togive 9.42 g (97% yield) of the title compound as a white solid. ESI MS:m/z 124.1 [M+H]⁺.

b. Dimethyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2,3-dicarboxylate

To a solution of1-amino-2,5-dimethylpyrazin-1-ium-2,4,6-trimethylbenzene-sulfonate (4.72g, 14.6 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassiumcarbonate (4.44 g, 32.1 mmol). The mixture was stirred at roomtemperature for 10 min. Then a solution of dimethyl but-2-ynedioate(1.87 g, 13.2 mmol) in DMF (30 mL) was added. The resulting mixture wasstirred at room temperature for 1 h. Then the mixture was poured intowater (400 mL), extracted with EtOAc (3×200 mL). The combined organiclayer was dried over sodium sulfate, filtered, evaporated, andchromatographed on silica gel using 20% ethyl acetate (EtOAc) inpetroleum ether (PE) as eluent to give 1.04 g (27% yield) of the titlecompound as a yellow solid. ESI MS: m/z 124.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.82 (d, J=0.8 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 2.81 (s,3H), 2.75 (s, 3H).

c. Methyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2-carboxylate

A solution of dimethyl4,7-dimethylpyrazolo[1,5-a]pyrazine-2,3-dicarboxylate (900 mg, 3.42mmol) in sulfuric acid (4 mL) and water (1 mL) was stirred and heated to180° C. After stirring for 2 h at that temperature, the reaction mixturewas cooled, and 40 mL of methanol (MeOH) was added. The mixture wasrefluxed at 70° C. for 2 h. Then the mixture was concentrated todryness. The residue was treated with water and adjusted with saturatedsodium bicarbonate solution to pH 8, then extracted with EtOAc (3×100mL). The combined organic layer was washed with brine, dried over sodiumsulfate, filtered, and evaporated to give 560 mg (80% yield) of thetitle compound as a yellow solid. ESI MS: m/z 206.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.73 (d, J=0.8 Hz, 1H), 7.36 (s, 1H), 4.03 (s, 3H), 2.77(s, 3H), 2.75 (s, 3H).

d. (4,7-Dimethylpyrazolo[1,5-a]pyrazin-2-yl)methanol

A solution of methyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2-carboxylate(62 mg, 0.30 mmol) in DCM (5 mL) was cooled to 0° C. Diisobutylaluminiumhydride (DIBAL-H) (1 M in cyclohexane, 1 mL, 0.33 mmol) was added to theabove solution dropwise over 5 min. After addition, the mixture wasstirred at 0° C. for 1 h. Saturated aqueous ammonium chloride solution(2 mL) was added to quench the reaction. Then 5 mL of saturated sodiumbicarbonate aqueous solution was added. The mixture was extracted withDCM (3×15 mL). The combined organic layer was washed with brine, driedover sodium sulfate, filtered, evaporated, and chromatographed on silicagel using 5% MeOH in DCM as eluent to give 41 mg (77% yield) of thetitle compound as a yellow solid. ESI MS: m/z 178.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.60 (s, 1H), 6.77 (s, 1H), 4.98 (d, J=6.0 Hz, 2H), 2.71(s, 3H), 2.67 (s, 3H).

e. 2-(Chloromethyl)-4,7-dimethylpyrazolo[1,5-a]pyrazine hydrochloride

A solution of (4,7-dimethylpyrazolo[1,5-a]pyrazin-2-yl)methanol (41 mg,0.23 mmol) in thionyl chloride (2 mL) was stirred at room temperaturefor 5 min. The mixture was concentrated to dryness to give 53 mg (100%yield) of the title compound as a yellow solid. ESI MS: m/z 196.1[M+H]⁺.

To a solution of 1,3-dichloropropan-2-one (1.40 g, 11 mmol) in1,2-dimethoxyethane (5 mL), pyridin-2-amine (0.94 g 10 mmol) was added.The solid dissolved immediately and a white precipitate was observed.The mixture was stirred at room temperature for 1 h, and then was cooledto 0° C. for 20 min. The resulting mixture was filtered to give a whitesolid. The precipitate was suspended in ethanol (EtOH) (40 mL) andheated at reflux to render a clear solution. After refluxing for 2 h,the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in water and saturated aqueous NaHCO₃ solution wasadded to adjust the pH to ˜7.0. A white suspension formed during thecourse of addition. The resulting mixture was stirred for 20 min andthen filtered to give the title compound as a white solid (0.5 g, 30%yield). ESI MS: m/z 167 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d,J=6.8 Hz, 1H), 7.97 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.23 (t, J=7.6 Hz,1H), 6.88 (t, J=6.4 Hz, 1H), 4.82 (s, 2H).

a. 3,6-Dimethylpyrazin-2-amine

A 100 mL autoclave vessel was charged with 3-chloro-2,5-dimethylpyrazine(25.0 g, 176 mmol), NH₃ (aq. 25˜28% w/w, 80 mL) and Cu powder (1.69 g,26.4 mmol) and the autoclave vessel was sealed. The resulting mixturewas heated to 150° C. and stirred vigorously for 48 h. The reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was diluted with brine (100 mL) and extracted withEtOAc (4×100 mL). The combined extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waswashed with PE to render the title compound as a light yellow solid(17.6 g, yield 81%). ESI MS: m/z 124 [M+H]⁺.

b. 2-(Chloromethyl)-5,8-dimethylimidazo[1,2-a]pyrazine

To a solution of 3,6-dimethylpyrazin-2-amine (1.0 g, 8.1 mmol) in EtOH(20 mL) was added 1,3-dichloropropan-2-one (1.03 g, 8.1 mmol). Thereaction mixture was stirred at reflux for 1 h. Then the solvent wasremoved. The product was purified by reverse column chromatography togive the title compound as a brown solid (570 mg, yield 85%). ESI MS:m/z 196 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.10 (s, 1H), 7.65 (s, 1H),4.94 (s, 2H), 2.70 (s, 3H), 2.54 (s, 3H).

a.1-Amino-3,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate

A solution of O-(mesitylsulfonyl)hydroxylamine (5.3 g, 24.6 mmol) in DCM(20 mL) was slowly added to a solution of 3,6-dimethylpyridin-2-amine(1.0 g, 8.2 mmol) in DCM (5 mL). A yellow precipitate was formedgradually, and after stirring for 1 h, the precipitate was collected byfiltration and used for the next step without further purification. ESIMS: m/z 138 [M+H]⁺.

b. 2-(Chloromethyl)-5,8-dimethyl[1,2,4]triazolo[1,5-a]pyridine

A suspension of1-amino-3,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate(crude product from the previous step, 8.2 mmol), methyl 2-chloroacetate(1.78 g, 16.4 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in EtOH(30 mL) was stirred at 80° C. for 16 h. After cooled to roomtemperature, the reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (eluting with 20% v/v EtOAcin PE) to give the title compound (920 mg, yield 36%, 2 steps). ESI MS:m/z 196, 198 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.24 (d, J=7.2 Hz, 1H),6.77 (d, J=7.2 Hz, 1H), 4.85 (s, 2H), 2.74 (s, 3H), 2.62 (s, 3H).

a.1-Amino-6-methylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate

A solution of O-(mesitylsulfonyl)hydroxylamine (6.45 g, 30.0 mmol) inDCM (30 mL) was stirred at room temperature, then2-amino-6-methylpyridine (1.08 g, 10.0 mmol) was added slowly. Thereaction mixture was stirred at room temperature for 12 h, and filteredto remove the solvent. A yellow solid was collected which was used forthe next step without further purification. ESI MS: m/z 124 [M+H]⁺.

b. 2-(Chloromethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

A suspension of1-amino-6-methylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate(520 mg, crude product from the previous step, 1.61 mmol), methyl2-chloroacetate (700 mg, 7.80 mmol) and potassium carbonate (444 mg,3.22 mmol) in EtOH (10 mL) was stirred at 80° C. for 16 h. After cooledto room temperature, the reaction mixture was concentrated and purifiedby silica gel column chromatography (eluting with EtOAc in PE, agradient from 17% to 30% v/v) to give the title compound (290 mg, yield84%). ESI MS: m/z 182, 184 [M+H]⁺.

a.1-Amino-3-methylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate

A solution of O-(mesitylsulfonyl)hydroxylamine (6.45 g, 30.0 mmol) inDCM (30 mL) was stirred at room temperature, then2-amino-3-methylpyridine (1.08 g, 10.0 mmol) was added slowly. Thereaction mixture was stirred at room temperature for 12 h, the solventwas removed under vacuum, and the crude product was used for the nextstep without further purification. ESI MS: m/z 124 [M+H]⁺.

b. 2-(Chloromethyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

A suspension of1-amino-3-methylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate(630 mg, crude product from the previous step, 1.95 mmol), methyl2-chloroacetate (423 mg, 3.90 mmol) and potassium carbonate (540 mg, 3.9mmol) in EtOH (10 mL) was stirred at 80° C. for 4 h. After cooled toroom temperature, the reaction mixture was concentrated and the residuewas purified by silica gel column chromatography (eluting with 25% v/vEtOAc in PE) to give the title compound (95 mg, yield 27%). ESI MS: m/z182, 184 [M+H]⁺.

a. 1-Aminopyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate

A mixture of pyridin-2-amine (6.6 g, 20.0 mmol) in DCM (15 mL) wasstirred at room temperature, and O-(mesitylsulfonyl)hydroxylamine (1.0g, 10.0 mmol) was added slowly. The reaction mixture was stirred at roomtemperature for 12 h, and the solvent was removed under vacuum. Thecrude product was used for next step without further purification. ESIMS: m/z 110 [M+H]⁺.

b. 2-(Chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine

A mixture of1-aminopyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crudeproduct from the previous step) and sodium hydroxide (NaOH) (0.55 g,13.8 mmol) in EtOH (30 mL) was stirred at 60° C. for 1 h, then methyl2-chloroacetate (1.12 g, 10.4 mmol) was added. The reaction mixture wasrefluxed for 4 h, then the solvent was removed. The product was purifiedby silica gel column chromatography (eluting with 20% v/v EtOAc in PE)to give the title compound (512 mg, yield: 29%, 2 steps). ESI MS: m/z168 [M+H]⁺.

c. [1,2,4]Triazolo[1,5-a]pyridin-2-ylmethanol

To a solution of1-aminopyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (1.24 g, 4mmol) in EtOH (15 mL) was added NaOH (320 mg, 8 mmol). The mixture washeated to 60° C. and stirred for 1 h. Then methyl 2-hydroxyacetate (720mg, 8 mmol) was added and the mixture was heated to 80° C. and stirredfor 3 h. The resulting mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was washed with water(10 mL) and extracted with DCM (15 mL×3). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the title compound as apale yellow solid (350 mg, 59% yield). ESI MS: m/z 150 [M+H]⁺.

d. [1,2,4]Triazolo[1,5-a]pyridine-2-carbaldehyde

To a solution of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (0.35 g, 2.3mmol) in EtOH (50 mL) was added manganese (IV) oxide (1.02 g, 11.5mmol). The mixture was refluxed for 2 days. After cooling to roomtemperature, the mixture was filtered through Celite. The filtrate wasconcentrated, and the residue was purified by reverse phase columnchromatography (eluting with 10% v/v acetonitrile in water, with 0.01%NH₃.H₂O) to afford the title compound (0.15 g, 43% yield) as a whitesolid. ESI MS: m/z 148 [M+H]⁺.

a.3-Amino-2,5-dimethylpyrimidin-4(3H)-iminium-2,4,6-trimethylbenzenesulfonate

A mixture of 2,5-dimethylpyrimidin-4-amine (15.2 g, 49.0 mmol) in DCM(30 mL) was stirred at room temperature, andO-(mesitylsulfonyl)hydroxylamine (2.0 g, 16.0 mmol) was added slowly.The reaction mixture was stirred at room temperature for 12 h, then thesolvent was removed under reduced pressure. The crude product was usedfor the next step without further purification. ESI MS: m/z 139 [M+H]⁺.

b. 2-(Chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-f]pyrimidine

A mixture of3-amino-2,5-dimethylpyrimidin-4(3H)-iminium-2,4,6-trimethylbenzenesulfonate(crude product from the previous step), NaOH (1.33 g, 33.1 mmol) in EtOH(100 mL) was stirred at 60° C. for 1 h, and then methyl 2-chloroacetate(10.8 g, 99.3 mmol) was added. The reaction mixture was stirred andrefluxed overnight, and then the solvent was removed under reducedpressure. The product was purified by silica gel column (eluting with20% v/v EtOAc in PE) to give the title compound (72 mg, yield 2%, 2steps). ESI MS: m/z 197 [M+H]⁺.

a.1-Amino-4,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate

A solution of O-(mesitylsulfonyl)hydroxylamine (1.65 g, 7.65 mmol) inDCM (20 mL) was stirred at room temperature, and 4,6-dimethylpyrimidine(0.313 g, 2.55 mmol) was added slowly. The reaction mixture was stirredat room temperature for 3 h, then the solvent was removed under reducedpressure, and the crude product was used for the next step withoutfurther purification. ESI MS: m/z 139 [M+H]⁺.

b. 2-(Chloromethyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

A suspension of1-amino-4,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate(crude product from the previous step, 2.55 mmol), methyl2-chloroacetate (550 mg, 5.10 mmol) and NaOH (410 mg, 10.20 mmol) inEtOH (10 mL) was stirred at 80° C. for 4 h. After cooled to roomtemperature, the reaction mixture was concentrated, and the residue waspurified by silica gel column chromatography (eluting with 25% v/v EtOAcin PE) to give the title compound (110 mg, yield 22%). ESI MS: m/z 197,199 [M+H]⁺.

(a) O-(Mesitylsulfonyl)hydroxylamine

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (30 g, 0.148mol) and tert-butyl hydroxycarbamate (18 g, 0.148 mol) in Et₂O (500 mL)was added Et₃N (15 g, 0.148 mol) dropwise over 1 h. The reaction mixturewas stirred at room temperature for 4 h, then filtered. The filtrate wasconcentrated. The product was purified by silica gel columnchromatography (5% v/v EtOAc in PE) to give tert-butylmesitylsulfonyloxycarbamate as a white solid (31 g, yield 72%). ESI MS:m/z 338 [M+Na]⁺.

A solution of tert-butyl mesitylsulfonyloxycarbamate (3 g, 9.5 mmol) intrifluoroacetic acid (7 mL) was stirred at 10° C. for 40 min, thenpoured into ice/water (10 mL) and the resulting solid was collected byfiltration. The solid was dissolved in DCM (12 mL), dried over Na₂SO₄,and filtered. The solution containing O-(mesitylsulfonyl)hydroxylaminewas used without further purification.

(b) 3,6-Dimethylpyrazin-2-amine

A mixture of 2,5-dimethylpyrazine (14 g, 0.13 mol) inN,N-dimethylaniline (50 mL) was heated to 170° C. and NaNH₂ (22 g, 0.56mol) was added in portions. The reaction mixture was stirred at 170° C.for 1 h, and the solvent was removed. The product was purified by silicagel column chromatography to give 3,6-dimethylpyrazin-2-amine as a brownsolid (1.6 g, yield 10%). ESI MS: m/z 124 [M+1]⁺.

(c)1-Amino-3,6-dimethylpyrazin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate

A mixture of 3,6-dimethylpyrazin-2-amine (1.23 g, 10 mmol) in DCM (20mL) was cooled to 0° C. and a solution ofO-(mesitylsulfonyl)hydroxylamine (4.3 g, 20 mmol) was added slowly. Thereaction mixture was allowed to warm to room temperature for 3 h andfiltered. The solid collected was washed with DCM (50 mL) to give1-amino-3,6-dimethylpyrazin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonateas a brown solid (2.0 g, yield 59%). ESI MS: m/z 139 [M+199]⁺.

(d) 2-(Chloromethyl)-5,8-dimethyl[1,2,4]triazolo[1,5-a]pyrazine

A mixture of1-amino-3,6-dimethylpyrazin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate(2.0 g, 5.9 mmol) and NaOH (480 mg, 12 mmol) in EtOH (20 mL) was stirredat 60° C. for 1 h. Methyl 2-chloroacetate (1.34 g, 12.4 mmol) was thenadded slowly. The reaction mixture was refluxed for 4 h, then thesolvent was removed. The product was purified by silica gel columnchromatography to give2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine as a yellowsolid (420 mg, yield 36.3%). ESI MS: m/z 197 [M+1]⁺.

(e)((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphoniumchloride

A mixture of2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (420 mg,2.14 mmol) and triphenylphosphine (672 mg, 2.57 mmol) in1,2-dichloroethane (10 mL) was heated to 140° C. in a microwave reactorfor 1 h. The reaction mixture was cooled to room temperature andconcentrated to give the title compound as a yellow solid (980 mg, yield100%). ESI MS: m/z 424 [M−35]⁺.

a. 8-Nitroquinolin-7-amine

To a solution of 8-nitroquinoline (1.88 g, 10 mmol) and1,1,1-trimethylhydrazinium iodide (3.03 g, 15 mmol) in anhydrousdimethyl sulfoxide (DMSO) (20 mL) was added potassium tert-butoxide(3.36 g, 30 mmol) as a solid. The mixture was stirred at roomtemperature for 1 h. The mixture was then poured into saturated aqueousammonium chloride and extracted with EtOAc. The organic layers wereconcentrated and the residue was purified by silica gel columnchromatography (eluting with PE/EtOAc v/v 2:1) to give8-nitroquinolin-7-amine as a yellow solid (300 mg, yield 18%). ESI MS:m/z 189 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.93 (dd, 1H, ¹J=3.2 Hz,²J=1.6 Hz), 8.00 (dd, 1H, ¹J=6.4 Hz, ²J=1.6 Hz), 7.69 (d, 1H, J=6.8 Hz),7.29 (dd, 1H, ¹J=6.0 Hz, ²J=3.2 Hz), 7.00 (d, 1H, J=7.2 Hz), 5.60 (s,2H).

b. N-Methyl-8-nitroquinolin-7-amine

To a solution of 8-nitroquinolin-7-amine (1.89 g, 10 mmol) intetrahydrofuran (THF) (10 mL) was added sodium hydride (60% wt inmineral oil, 800 mg, 20 mmol). The mixture was stirred at roomtemperature for 30 minutes, then iodomethane (1.42 g, 10 mmol) wasadded. The mixture was stirred at room temperature for 5 h. Then water(10 mL) was added. The mixture was extracted with EtOAc, and the organiclayer was concentrated. The residue was purified by silica gel columnchromatography (eluting with PE/EtOAc v/v 2:1) to giveN-methyl-8-nitroquinolin-7-amine as a yellow solid (1.6 g, yield 79%).ESI MS: m/z 204 [M+H]⁺.

c. N⁷-Methylquinoline-7,8-diamine

To a solution of N-methyl-8-nitroquinolin-7-amine (1.6 g, 7.9 mmol) inMeOH (25 mL) was added hydrazine hydrate (2.25 g, 455 mmol) and Raney Ni(8 drops). The mixture was stirred at room temperature for 20 minutes.The catalyst was removed by filtration and the filtrate was concentratedto give N⁷-methylquinoline-7,8-diamine as a yellow solid (1.2 g, yield80%). ESI MS: m/z 174 [M+H]⁺.

d. (3-Methyl-3H-imidazo[4,5-h]quinolin-2-yl)methanol

A mixture of N⁷-methylquinoline-7,8-diamine (1.0 g, 5.8 mmol) and2-hydroxy acetic acid (2.2 g, 29 mmol) was stirred at 115° C. for 2 h.Then saturated sodium bicarbonate solution was added. The mixture wasextracted with EtOAc. The organic layer was concentrated to give aresidue which was purified by silica gel column chromatography (elutingwith DCM/MeOH v/v 30:1) to give(3-methyl-3H-imidazo-[4,5-h]quinolin-2-yl)methanol as a yellow solid(1.0 g, yield 83%). ESI MS: m/z 214 [M+H]⁺.

e. 3-Methyl-3H-imidazo[4,5-h]quinoline-2-carbaldehyde

To a solution of (3-methyl-3H-imidazo[4,5-h]quinolin-2-yl)methanol (560mg, 2.62 mmol) in DCM (10 mL) was added manganese (IV) oxide (2.28 g,26.2 mmol). The mixture was stirred at room temperature for 12 h. Thesolid was removed by filtration and the filtrate was concentrated. Thecrude product was purified by silica gel column chromatography (elutingwith PE/EtOAc v/v 2:1) to give3-methyl-3H-imidazo[4,5-h]quinoline-2-carbaldehyde as a yellow solid(370 mg, yield: 67.5%). ESI MS: m/z 212 [M+H]⁺.

f. 3-Methyl-3H-imidazo[4,5-f]quinoline-2-carbaldehyde

The methyl and desmethyl imidazo[4,5-f]quinoline were prepared usingsimilar chemical procedures of the above steps of General Procedure K(e.g., steps a to e). In the above scheme, the crude aldehyde waspurified by column chromatography (eluting with PE/EtOAc v/v 2:1) togive 3-methyl-3H-imidazo[4,5-f]quinoline-2-carbaldehyde as a yellowsolid. ESI MS: m/z 212 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 10.19 (s, 1H),9.02-8.99 (m, 1H), 8.99 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.79 (d, J=5.2Hz, 1H), 7.63 (dd, J=7.8, 4.2 Hz, 1H), 4.30 (s, 3H).

a. 6-Nitroquinoxaline

A suspension of 4-nitrobenzene-1,2-diamine (15.3 g, 0.1 mol) andoxalaldehyde (40% in water, 17.4 g, 0.12 mol) in EtOH (150 mL) wasstirred at reflux for 16 h. The mixture was then filtered, and the solidwas collected to give 6-nitroquinoxaline as a yellow solid (17.0 g,yield 97%). ESI MS: m/z 176.0 [M+H]⁺.

b. Quinoxalin-6-amine

To a solution of 6-nitroquinoxaline (17.0 g, 0.097 mol) in MeOH (500 mL)was added hydrazine hydrate (19.4 g, 0.39 mol) and Raney Ni (2.0 g). Themixture was stirred at room temperature for 1 h. The mixture was thenfiltered, and the filtrate was concentrated under reduce pressure togive quinoxalin-6-amine as a yellow solid (14.0 g, yield 99%). ESI MS:m/z 146.1 [M+H]⁺.

c. N-(Quinoxalin-6-yl)acetamide

A solution of quinoxalin-6-amine (14.0 g, 0.97 mol) in acetic anhydride(120 mL) was stirred at 100° C. for 1 h. Excess acetic anhydride wasremoved under reduced pressure. To the residue was added 150 mL ofsaturated aqueous sodium bicarbonate solution. The mixture was extractedwith DCM (3×150 mL), and the combined organic layers were dried oversodium sulfate and concentrated under reduce pressure to giveN-(quinoxalin-6-yl)acetamide as a yellow solid (8.4 g, yield 47%). ESIMS: m/z 188.1 [M+H]⁺.

d. N-Methyl-N-(quinoxalin-6-yl)acetamide

To a solution of N-(quinoxalin-6-yl)acetamide (8.0 g, 0.043 mol) in THF(120 mL) was added sodium hydride (60% wt in mineral oil, 3.42 g, 0.086mol). The mixture was stirred at room temperature for 10 min. Theniodomethane (7.28 g, 0.051 mol) was added. The mixture was stirred atroom temperature for 2 h. Water (60 mL) was added carefully. The mixturewas extracted with EtOAc (3×150 mL). The extracts were dried over sodiumsulfate, concentrated to give N-methyl-N-(quinoxalin-6-yl)acetamide as abrown solid (8.04 g, yield 93%). ESI MS: m/z 202.1 [M+H]⁺.

e. N-Methyl-5-nitroquinoxalin-6-amine

To a solution of N-methyl-N-(quinoxalin-6-yl)acetamide (4.02 g, 0.02mol) in DCM (60 mL) was added a solution of potassium nitrate (4.02 g,0.04 mol) in sulfuric acid (10 mL) cooled to 0° C. The mixture was thenwarmed and stirred at room temperature for 4 h. Water (20 mL) was added.The mixture was adjusted to pH ˜9 with saturated NaOH aqueous solution.Then the mixture was extracted with EtOAc (5×150 mL). The extracts weredried over sodium sulfate and concentrated to give the crude product,which was purified by silica gel column chromatography (eluting withPE/EtOAc v/v 2:1) to give N-methyl-5-nitroquinoxalin-6-amine as a yellowsolid (1.4 g, yield 35%). ESI MS: m/z 205.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.85 (d, J=1.6 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.07 (d, J=9.6Hz, 1H), 7.67 (brs, 1H), 7.41 (d, J=9.2 Hz, 1H), 3.18 (s, 3H).

f. N⁶-Methylquinoxaline-5,6-diamine

To a solution of N-methyl-5-nitroquinoxalin-6-amine (1.3 g, 6.4 mmol) inMeOH (100 mL) was added hydrazine hydrate (1.27 g, 25.5 mmol) and RaneyNi (0.2 g). The mixture was stirred at room temperature for 1 h. Themixture was then filtered, and the filtrate was concentrated underreduce pressure to give N⁶-methylquinoxaline-5,6-diamine as a blacksolid (1.14 g, yield 100%). ESI MS: m/z 175.1 [M+H]⁺.

g. (3-Methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol

A mixture of N⁶-methylquinoxaline-5,6-diamine (1.14 g, 6.4 mmol) and2-hydroxyacetic acid (486 mg, 6.4 mmol) was stirred at 110° C. for 2 h.Then the mixture was purified by silica gel column chromatography(eluting with DCM/MeOH v/v 30:1) to give(3-methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol as a yellow solid(880 mg, yield 39%). ESI MS: m/z 215.1 [M+H]⁺.

h. 3-Methyl-3H-imidazo[4,5-f]quinoxaline-2-carbaldehyde

To a solution of (3-methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol(880 mg, 4.03 mmol) in DCM (100 mL) was added activated manganese (IV)dioxide (3.5 g, 40.3 mmol). The mixture was stirred at room temperaturefor 16 h. Then the mixture was filtered and the filtrate wasconcentrated under reduce pressure to give the crude product, which waspurified by silica gel column (eluting with DCM/MeOH v/v 30:1) to give3-methyl-3H-imidazo[4,5-f]quinoxaline-2-carbaldehyde as a yellow solid(310 mg, yield 36%). ESE MS: m/z 213.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):δ 10.25 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.15(d, J=9.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 4.33 (s, 3H).

a. 2-((Trimethylsilyl)ethynyl)nicotinonitrile

To a solution of 2-chloronicotinonitrile (21.6 g, 156 mmol) in toluene(200 mL) was added Pd(dppf)Cl₂ (2.3 g, 3.12 mmol), copper (I) iodide(594 mg, 3.12 mmol), triethylamine (32 mL, 312 mmol) andethynyltrimethylsilane (23 g, 234 mmol). The reaction mixture wasstirred at 70° C. under N₂ for 5 h. The reaction mixture was filteredthrough a Celite pad. The filtrate was concentrated under reducedpressure to give a residue. 40 mL of water was added to the residue, andthe mixture was extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine (1×100 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by silica gel columnchromatography (eluting with a gradient of PE/EtOAc v/v 40:1, 20:1,10:1, 5:1) to yield 2-((trimethylsilyl)ethynyl)nicotinonitrile as ayellow solid (19.14 g, yield 61%). ESI MS: m/z 201 [M+H]⁺.

b. 2-(2,2-Dimethoxyethyl)nicotinonitrile

To a solution of 2-((trimethylsilyl)ethynyl)nicotinonitrile (19.14 g,95.7 mmol) in MeOH (200 mL) was added sodium methanolate (16.5 g, 306.2mmol). The reaction mixture was refluxed at 80° C. for 14 h under N₂.After removal of the MeOH, the residue was diluted with H₂O andextracted with DCM (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude product. The crudeproduct was purified by silica gel column chromatography (eluting withDCM) to yield 2-(2,2-dimethoxyethyl)nicotinonitrile as a yellow oil(13.76 g, yield 75%). ESI MS: m/z 193 [M+H]⁺.

c. 2-(2,2-Dimethoxyethyl)nicotinamide

A mixture of 2-(2,2-dimethoxyethyl)nicotinonitrile (7 g, 36.42 mmol),aqueous Na₂CO₃ (3 N, 145 mL), H₂O₂ (15%, 145 mL) in acetone (73 mL) wasstirred at room temperature for 14 h. After removal of acetone, theresidue was diluted with water and extracted with DCM (3×100 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure togive the crude product. The crude product was purified by silica gelcolumn chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc) toyield 2-(2,2-dimethoxyethyl)nicotinamide as a solid (6 g, yield 78%).ESI MS: m/z 211 [M+H]⁺, 233 [M+Na]⁺.

d. 1,6-Naphthyridin-5(6H)-one

A mixture of 2-(2,2-dimethoxyethyl)nicotinamide (8.33 g, 39.7 mmol) andTsOH.H₂O (940 mg) in toluene (100 mL) was refluxed for 14 h. Toluene wasremoved under reduced pressure, then the residue was purified by silicagel column chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc)to yield 1,6-naphthyridin-5(6H)-one as a light yellow solid (3.87 g,yield 66%). ESI MS: m/z 147 [M+H]⁺.

e. 5-Chloro-1,6-naphthyridine

A solution of 1,6-naphthyridin-5(6H)-one (500 mg, 3.42 mmol) in POCl₃(10 mL) was stirred at 100° C. for 14 h. POCl₃ was removed under reducedpressure. The residue was dissolved with DCM (40 mL), and the solutionwas stirred at 0° C. Then aqueous Na₂CO₃ was added cautiously to adjustpH to 6-7. Then the organic phase was separated from the aqueous phase,and the aqueous phase was extracted with EtOAc (4×15 mL). The combinedorganic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to give5-chloro-1,6-naphthyridine as a yellow solid (533 mg, yield 95%). ESIMS: m/z 165 [M+H]⁺.

f. 5-Azido-1,6-naphthyridine

A solution of 5-chloro-1,6-naphthyridine (500 mg, 3.04 mmol) in DMF (5mL) was stirred at room temperature. Sodium azide (592 mg, 9.12 mmol)was added to the mixture, and the mixture was stirred at 80° C. for 4 h.The mixture was cooled to room temperature and filtered through Celiteto remove a white solid. The filtrate was diluted with EtOAc (25 mL) andwashed with brine (5×5 mL). The combined organic layers were dried withNa₂SO₄, filtered, and the solvent was removed under reduced pressure toyield 5-azido-1,6-naphthyridine as a yellow solid, which was used in thenext step without further purification (500 mg, yield 96%). ESI MS: m/z172 [M+H]⁺.

g. 1,6-Naphthyridin-5-amine

A solution of 5-azido-1,6-naphthyridine (3.2 g, 18.7 mmol) in MeOH (30mL) was stirred at room temperature. SnCl₂.2H₂O (21 g, 93.6 mmol) wasadded to the mixture, followed by the addition of concentrated HCl (10mL), then the mixture was refluxed for 5 h. The mixture was cooled toroom temperature, and neutralized with sat. NaHCO₃ to adjust the pH to7-8. The mixture was filtered, and the aqueous phase was extracted withEtOAc (5×30 mL). The combined organic layers were dried with Na₂SO₄,filtered, and the solvent was removed under reduced pressure to yield1,6-naphthyridin-5-amine as a pale yellow solid, which was used in thenext step without further purification (2.20 g, yield 81%). ESI MS: m/z146 [M+H]⁻. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (dd, ¹J=1.6 Hz, ²J=4.8 Hz,1H), 8.62 (d, J=8.0 Hz, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.47 (dd, ¹J=4.8Hz, ²J=8.0 Hz, 1H), 7.09 (br, 2H), 6.98 (d, J=6.0 Hz, 1H).

h.6-Amino-1,6-naphthyridin-5(6H)-iminium-2,4,6-trimethylbenzenesulfonate

To trifluoroacetic acid (10 mL), stirred at 0° C., was added tert-butylmesitylsulfonyloxycarbamate (6.50 g, 20.6 mmol), and the mixture wasstirred at 0° C. for 30 min. The mixture was poured into ice-water (10mL). A white precipitate was formed, which was filtered and collected.The white precipitate was dissolved in DCM (20 mL), and dried withNa₂SO₄. To the DCM solution was added 1,6-naphthyridin-5-amine (1.0 g,6.88 mmol), and the mixture was stirred at room temperature for 4 h. Thesolvent was removed under reduced pressure and the residue was washedwith Et₂O (3×15 mL). The yellow solid obtained was used in the next stepwithout further purification (3.30 g). ESI MS: m/z 161 [M+H]⁺.

i. 2-(Dichloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

A mixture of6-amino-1,6-naphthyridin-5(6H)-iminium-2,4,6-trimethylbenzene-sulfonate(3.30 g, 9.17 mmol), methyl 2,2-dichloroacetate (3.93 g, 27.5 mmol) andK₂CO₃ (3.80 g, 27.5 mmol) in EtOH (30 mL) was refluxed for 14 h. Themixture was then cooled to room temperature, filtered, and washed withDCM (3×20 mL). The combined organic layers were concentrated underreduced pressure. The residue was dissolved in EtOAc (100 mL), washedwith brine (5×10 mL), dried with Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel column chromatography using DCM aseluent to yield2-(dichloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine as a whitesolid (500 mg, yield 29%). ESI MS: m/z 253, 255 [M+H]⁺.

j. [1,2,4]Triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde

A microwave tube was charged with a mixture of2-(dichloromethyl)-[1,2,4]triazolo [5,1-f][1,6]naphthyridine (180 mg,0.71 mmol) in dimethylamine in water (5 mL, 33% wt in water) and heatedat 70° C. in oil bath for 5 h, and then cooled to room temperature. Themixture was extracted with EtOAc (3×20 mL). The combined organic layerwas dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography (eluting with DCM/MeOH v/v100/1 and 50/1) to yield[1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde as a white solid(85 mg, yield 60%). ESI MS: m/z 199 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ10.22 (s, 1H), 9.06 (m, 1H), 8.97 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 7.65(m, 2H).

a.(E)-2-(2-(5-Methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

To a solution of [1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde(20 mg, 0.1 mmol) in THF (1 mL) was added a solution of((5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)triphenylphosphoniumchloride (49 mg, 0.11 mmol) in DCM (3 mL), followed by the addition ofDBU (45 mg, 0.3 mmol) at 0° C. under N₂. The resulting mixture wasstirred for 4 h at room temperature and diluted with DCM (15 mL). Themixture was washed with water (10 mL), brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a crude residue,which was purified by prep. TLC to afford the title compound (17 mg,yield 52%). ESI MS: m/z 328 [M+H]⁺.

b.2-(2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)ethyl)-5,6-dihydro-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

To a solution of(E)-2-(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine(17 mg, 0.52 mmol) in MeOH (3 mL) and aqueous NaOH (1 N, 1 mL) was added10% Pd/C (17 mg) under a nitrogen atmosphere. The reaction vessel wasdegassed for three times, followed by treatment with H₂ for 1 h at roomtemperature. The mixture was then submitted for prep-HPLC purificationto give a free base of the title compound as a white solid. The solidwas triturated with a solution of HCl (gas) in EtOAc (2 mL) to affordthe di-HCl salt of the title compound as a yellow solid (7.83 mg, yield37%). ESI MS: m/z 332 [M+H]⁺.

a. 1,7-Naphthyridin-8-amine

A mixture of pyridine-2,3-diamine (5.0 g, 45.9 mmol), glycerol (21.1 g,229 mmol), sodium 3-nitrobenzenesulphonate (20.6 g, 91.7 mmol), sulfuricacid (20 mL) and water (30 mL) was heated to 135° C. and stirred for 16h. The mixture was cooled to room temperature and then poured intoice/water (150 g). The mixture was adjusted to pH ˜9 with saturated NaOHaqueous solution. Then the mixture was extracted with EtOAc (3×100 mL).The combined organic layers were dried over sodium sulfate andconcentrated under reduce pressure to give the crude product, which waspurified by silica gel column (eluting with PE/EtOAc v/v 2:1) to give1,7-naphthyridin-8-amine as a yellow solid (2.6 g, yield 39%). ESI MS:m/z 146.1 [M+H]⁺.

b. 8-Imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzenesulfonate

To a solution of 1,7-naphthyridin-8-amine (600 mg, 4.13 mmol) in DCM (5mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (2.7 g,12.4 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at 0° C. for2 h. The precipitate was filtered and collected to give8-imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzenesulfonate asa brown solid (1.2 g, yield 67%). ESI MS: m/z 161.1 [M+H]⁺.

c. [1,2,4]Triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol

To a suspension of8-imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzene-sulfonate(1.2 g, 2.83 mmol) in EtOH (30 mL) was added NaOH (227 mg, 5.67 mmol).The mixture was stirred at 60° C. for 1 h. Then methyl 2-hydroxyacetate(773 mg, 8.50 mmol) was added. The resulting mixture was stirred atreflux for 2 h. The mixture was concentrated and purified by silica gelcolumn chromatography (eluting with DCM/MeOH v/v 30:1) to give[1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol as a yellow solid(280 mg, yield 49%). ESI MS: m/z 201.1 [M+H]⁺,

d. [1,2,4]Triazolo[1,5-h][1,7]naphthyridine-2-carbaldehyde

To a solution of [1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol(280 mg, 1.4 mmol) in EtOH (20 mL) was added activated manganese (IV)dioxide (1.21 g, 14.0 mmol). The mixture was stirred at reflux for 2 h.Then the mixture was filtered and the filtrate was concentrated underreduce pressure to give[1,2,4]triazolo[1,5-h][1,7]naphthyridine-2-carbaldehyde as a yellowsolid (280 mg, yield 88%). ESI MS: m/z 199.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 10.34 (s, 1H), 9.16 (dd, J=1.6, 4.4 Hz, 1H), 8.55 (d, J=7.2 Hz,1H), 8.28 (dd, J=1.6, 8.0 Hz, 1H), 7.76 (dd J=4.4, 8.0 Hz, 1H), 7.47 (d,J=8.8 Hz, 1H).

a. Pyridine-2,5-diamine

To a solution of 5-nitropyridin-2-amine (6.95 g, 50.0 mmol) in MeOH (100mL) was added hydrazine hydrate (5.00 g, 100.0 mmol) and Raney Ni (700mg). The mixture was stirred at room temperature for 2 h. The catalystwas then removed by filtration and the filtrate was concentrated to givethe crude product as a dark oil (5.2 g, yield 68%). ESI MS: m/z 110[M+H]⁺.

b. 1,5-Naphthyridin-2-amine

A mixture of pyridine-2,5-diamine (5.2 g, 33.9 mmol), glycerol (15.6 g,169.5 mmol), sodium 3-nitrobenzenesulphonate (15.2 g, 67.8 mmol),sulfuric acid (20 mL) and water (30 mL) was heated to 135° C. andstirred for 16 h. The mixture was cooled to room temperature and thenpoured into ice/water (150 g). The pH of the mixture was adjusted to ˜9with saturated aqueous NaOH solution. Then the mixture was extractedwith EtOAc (3×100 mL) and the combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduce pressure to givethe crude product, which was purified by silica gel columnchromatography (eluting with DCM/MeOH v/v 20:1) to afford the product asa yellow solid (2.0 g, yield 41%). ESI MS: m/z 146 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 8.50 (dd, J=1.6 Hz, 4.4 Hz, 1H), 7.94 (d, J=8.8 Hz,1H), 7.82-7.80 (m, 1H), 7.47 (dd, J=4.0 Hz, 8.4 Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 6.72 (s, 2H).

c.1-Amino-1,5-naphthyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate

To a solution of 1,5-naphthyridin-2-amine (2.0 g, 13.8 mmol) in DCM (10mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (8.9 g,41.3 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for3 h. The precipitate was filtered and collected to give the crudeproduct as a yellow solid (4.2 g, yield 85%). ESI MS: m/z 161 [M+H]⁺.

d. 2-(Dichloromethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine

A suspension of1-amino-1,5-naphthyridin-2(1H)-iminium-2,4,6-trimethyl-benzenesulfonate(crude product from the previous step, 3.0 mmol), methyl2,2-dichloroacetate (0.86 g, 6.0 mmol) and potassium carbonate (0.62 g,4.5 mmol) in EtOH (30 mL) was stirred at 80° C. for 16 h. After cooledto room temperature, the reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (eluting with2% v/v MeOH in DCM) to give the title compound as a purple solid (300mg, yield 39%). ESI MS: m/z 253, 255 [M+H]⁺.

e. [1,2,4]Triazolo[1,5-a][1,5]naphthyridine-2-carbaldehyde

A suspension of2-(dichloromethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine (115 mg,0.455 mmol) in aqueous dimethylamine (3 mL, 33% wt in water) was heatedto 70° C. for 3 h. The mixture was cooled to room temperature, dilutedwith DCM (10 mL), filtered through a short plug filled with silica gelto remove basic impurities, and concentrated to give the title compoundas a white solid (65 mg, yield 72%). ESI MS: m/z 199 [M+H]⁺.

a. 2-Nitrothieno[2,3-b]pyridin-3-amine

To a solution of 2-mercaptonicotinonitrile (1 g, 7.4 mmol) in DMF (20mL) was added a solution of NaOH (0.88 g, 22 mmol) in water (5 mL) at 0°C. The mixture was stirred for 20 min, then bromonitromethane (2 g, 14.7mmol) was added dropwise. The resulting mixture was stirred for 1 h at0° C., diluted with water (100 mL), and filtered. The filter cake waswashed with water (20 mL×3) to give a yellow solid (1.1 g, yield 78%),which was used in the next step without further purification. ESI MS:m/z 196 [M+H]⁺.

b. Thieno[2,3-b]pyridine-2,3-diamine HCl Salt

To a suspension of 2-nitrothieno[2,3-b]pyridin-3-amine (1.1 g, 5.6 mmol)in EtOH (60 mL) was added Raney Ni (1 g), followed by slow addition ofN₂H₄.H₂O (1.4 g, 22 mmol). The mixture was stirred at room temperaturefor 2 h. A solution of HCl in EtOAc (1 M, 18 mL, 18 mmol) was added tothe reaction mixture slowly, and the mixture was filtered. The filtercake was washed with EtOAc (20 mL×3), then dried under reduced pressureto give the crude product as a yellow solid (2.7 g). ESI MS: m/z 166[M+H]⁺.

c. 3H-Thieno[2,3-b]pyridine[2,3-d]imidazole

A suspension of thieno[2,3-b]pyridine-2,3-diamine HCl salt (2.7 g, crudefrom the previous step, 5.6 mmol) and methyl orthoformate (3 mL) in MeOH(10 mL) was heated at reflux overnight, then concentrated to give thecrude residue as a yellow solid, which was used in the next step withoutfurther purification (900 mg, yield 92%). ESI MS: m/z 176 [M+H]⁺.

d. 3-Methyl-3H-thieno[2,3-b]pyridine[2,3-d]imidazole

To a solution of 3H-thieno[2,3-b]pyridine[2,3-d]imidazole (900 mg, 5.14mmol) in DMF (5 mL) was added sodium hydride (60% wt in mineral oil, 412mg, 10.3 mmol) slowly at 0° C. The mixture was stirred for 0.5 h thentreated with methyl iodide (730 mg, 5.14 mmol) at 0° C., and theresulting mixture was stirred for 16 h. The mixture was diluted with DCM(15 mL), washed with water (15 mL×3), brine (15 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated to give a crude residue,which was purified by prep. HPLC to afford the title compound as ayellow solid (194 mg, yield 20%). ESI MS: m/z 190 [M+H]⁺.

e. 3-Formyl-3H-thieno[2,3-b]pyridine[2,3-d]imidazole

To a pre-cooled solution of3-methyl-3H-thieno[2,3-b]pyridine[2,3-d]imidazole (57 mg, 0.3 mmol) inTHF (2.0 mL) was added n-BuLi (0.48 mL, 1.2 mmol) at 78° C. and themixture was stirred for 0.5 h. The mixture was then treated with asolution of DMF (44 mg, 0.6 mmol) in THF (0.5 mL) at −78° C., and theresulting mixture was stirred for 1 h at −78° C., then allowed to warmto room temperature. The reaction mixture was quenched with sat.ammonium chloride (5 mL), diluted with DCM (10 mL), washed with water (5mL), brine (15 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give a crude residue, which was used in the next stepwithout further purification (50 mg, yield 51%). ESI MS: m/z 218 [M+H]⁺.See, e.g., J. Het. Chem., 1975, 119-22; Chem. Pharm. Bull., 1985, 33,626-33.

a. Ethyl imidazo[1,2-a]pyridine-2-carboxylate

A solution of 2-aminopyridine (5.0 g, 53.2 mmol) in THF (150 mL) wastreated with ethyl bromopyruvate (10.32 g, 57.0 mmol) at roomtemperature followed by heating the mixture at reflux for 16 h. Theresulting white precipitate was collected by filtration and washed withTHF (10 mL). Recrystallization of the solids from boiling EtOH (20 mL)gave ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.10 g, 60% yield). ESIMS: m/z 191 [M+1]⁺. See, e.g., J. Med. Chem., 2003, 46, 3914-29.

b. Imidazo[1,2-a]pyridin-2-ylmethanol

To an ice-cold solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate(6.1 g, 32 mmol) in dry THF (300 mL) was added lithium aluminium hydride(LAH) (2.4 g, 64 mmol) in portions, and the temperature was maintainedat <5° C. for 2 h. THF and water (50 mL, 1:1 v/v) were added slowly andthe mixture was filtered. The filtrate was evaporated to dryness. Theresidue was re-dissolved in EtOAc (60 mL), and washed with brine (10mL×3). The organic layers were combined, and the solvent was removed togive the title compound (4.3 g, yield 90%). ESI MS: m/z 149 [M+H]⁺.

c. Imidazo[1,2-a]pyridine-2-carbaldehyde

To a solution of imidazo[1,2-a]pyridin-2-ylmethanol (3.0 g, 20 mmol) inEtOH (50 mL) was added manganese (IV) oxide (8.8 g, 100 mmol). Themixture was refluxed for 2 days. After cooling to room temperature, themixture was filtered through Celite, and the filtrate was concentrated.The residue was purified by reverse phase column chromatography (elutingwith acetonitrile in water 25% v/v, with 0.01% NH₃.H₂O) to afford thetitle compound (0.45 g, 15% yield) as a yellow solid. ESI MS: m/z 147[M+H]⁺.

Dimerized triazolopyrazine was prepared by the following method: theWittig reagent prepared from General Procedure J was employed as thestarting material. In the course of a subsequent reaction with an arylhalide (RCHO), the dimerized triazolopyridine was formed as a by-productin about 20% yield. The olefin by-product was purified by flash columnchromatography and reduced using standard protocols to afford the dimercompound.

a. Ethyl 3,4-dihydroxy-2-nitrobenzoate

To a solution of ethyl 3,4-dihydroxybenzoate (9.5 g, 52.2 mmol),isopropyl nitrate (13.5 g, 130.5 mmol), and tetrabutylammoniumhydrogensulfate (0.884 g, 2.61 mmol) in DCM (100 mL), was added sulfuricacid (14.25 g, 145.6 mmol) slowly at 0° C. The reaction mixture waswarmed to room temperature and stirred for 45 min, then quenched withice/water (150 mL), and extracted with DCM (150 mL×2). The extracts werecombined, and the solvent removed under vacuum. The product was purifiedby silica gel column (20% v/v EtOAc in PE) to give ethyl3,4-dihydroxy-2-nitrobenzoate (4.97 g, 40% yield). ESI MS: m/z 228[M+H]⁺.

b. Ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate

A mixture of ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 21.9 mmol),1,2-dibromoethane (6.70 g, 43.8 mmol), and potassium carbonate (6.04 g,43.8 mmol) in DMF (100 mL) was stirred at 80° C. overnight. To thereaction mixture was added ice/water (100 mL), and the resulting mixturewas extracted with EtOAc (200 mL×2). The extracts were combined anddried, and the solvent removed. The product was purified by silica gelcolumn (10% v/v EtOAc in PE) to give ethyl5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (4.30 g, 78%yield). ESI MS: m/z 254 [M+H]⁺.

c. 5-Nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid

A mixture of ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate(4.30 g, 17.0 mmol) and lithium hydroxide (2.86 g, 68 mmol) inacetonitrile (20 mL) and water (20 mL) was stirred at room temperaturefor 6 h. The acetonitrile was then removed, and the resulting mixturewas extracted with EtOAc (100 mL×2). The extracts were combined anddried, and the solvent removed. The crude product was used in the nextstep without further purification. ESI MS: m/z 226 [M+H]⁺.

d. tert-Butyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate

A mixture of 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid(3.80 g, 16.9 mmol), diphenylphosphoryl azide (5.10 g, 18.6 mmol) andtriethylamine (1.88 g, 18.6 mmol) in tert-butanol (50 mL) was stirred at100° C. for 16 h. The reaction mixture was cooled to 20° C., and thesolvent removed. The residue was dissolved in DCM (150 mL) and washedwith water (150 mL×2), and the solvent was removed. The residue waspurified by silica gel column (10% v/v EtOAc in PE) to give tert-butyl5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (2.30 g, 46%yield). ESI MS: m/z 297 [M+H]⁺.

e. tert-Butylmethyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate

A mixture of tert-butyl5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (2.3 g, 7.8 mmol)in DMF (25 mL) was stirred at 0° C. Sodium hydride (373 mg, 9.3 mmol)was added slowly. Dimethyl sulfate (1.017 g, 9.3 mmol) was addeddropwise and the mixture was stirred at 0° C. for 0.5 h. To the reactionmixture was slowly added water (40 mL). The mixture was extracted withtoluene (40 mL), the organic phase was washed with water (40 mL) anddried, and the solvent removed. The product was purified by silica gelcolumn (5% v/v EtOAc in PE) to give tert-butylmethyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate (2.2 g, 92%yield). ESI MS: m/z 311 [M+H]⁺.

f. N-Methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine

tert-Butyl methyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate(2.2 g, 7.1 mmol) in 2.0 M hydrochloric acid in Et₂O (30 mL) was stirredat room temperature for 3 h. The volatiles were removed to giveN-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (1.42 g, 95%yield). ESI MS: m/z 211 [M+H]⁺.

g. N-6-Methyl-2,3-dihydrobenzo[b][1,4]dioxine-5,6-diamine

A mixture of N-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine(1.42 g, 6.7 mmol) and Raney Ni (192 mg) in THF (40 mL) was stirred atroom temperature. Hydrazine hydrate (1.14 g, 22.86 mmol) was addeddrop-wise. The reaction mixture was stirred at room temperature for 1 h,then filtered, and the solvent removed to give the crude product. Thecrude product was purified by silica gel column (20% v/v EtOAc in PE) togive N-6-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5,6-diamine (1.0 g, 83%yield). ESI MS: m/z 181 [M+H]⁺.

a. 6-Nitro-1,2,3,4-tetrahydronaphthalene and5-nitro-1,2,3,4-tetrahydronaphthalene

To a solution of 1,2,3,4-tetrahydronaphthalene (26.4 g, 200 mmol) inEt₂O (200 mL) was added acetic anhydride (67 mL, 760 mmol) and cupricnitrate trihydrate (48.4 g, 200 mmol). The resulting mixture was stirredat room temperature for 16 h. After filtration, the filtrate wasconcentrated, and the residue was purified by silica gel column(PE/EtOAc v/v 100:2) to give a yellow oil (5.5 g, yield 15.6%) as amixture of 6-nitro-1,2,3,4-tetrahydronaphthalene and5-nitro-1,2,3,4-tetrahydronaphthalene, which was used in the next step.ESI MS: m/z 178 [M+H]⁺.

b. 5,6,7,8-Tetrahydronaphthalen-2-amine

To a solution of 6-nitro-1,2,3,4-tetrahydronaphthalene and5-nitro-1,2,3,4-tetrahydronaphthalene (5.5 g, 31.1 mmol) in MeOH (50 mL)was added 10% palladium on carbon (3.18 g, 3.0 mmol) under nitrogen,then replaced with hydrogen atmosphere (2 L). The resulting mixture wasstirred at room temperature for 16 h, and filtered through Celite. Thefiltrate was concentrated, and the residue was purified by silica gelcolumn (PE/EtOAc v/v 10:1) to give 5,6,7,8-tetrahydronaphthalen-2-amineas a white solid (2 g, 40% yield). ESI MS: m/z 148 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 6.88 (d, J=8.0 Hz, 1H), 6.49 (dd, J=2.0 Hz, J=8.0 Hz,1H), 6.44 (d, J=2.0 Hz, 1H), 3.49 (s, 2H), 2.69-2.67 (m, 4H), 1.78-1.75(m, 4H).

c. N-(1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide

To a solution of 5,6,7,8-tetrahydronaphthalen-2-amine (2 g, 13.6 mmol)in Et₂O (50 mL) was added acetic anhydride (4.6 mL, 51.7 mmol) andcupric nitrate trihydrate (3.3 g, 13.6 mmol). The resulting mixture wasstirred at room temperature for 4 h and filtered. The filtrate wasconcentrated, and the residue was purified by silica gel columnchromatography (PE/EtOAc v/v 5:1) to giveN-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide as a white solid(800 mg, 25% yield). ESI MS: m/z 235 [M+H]⁺.

d. N-Methyl-1-nitro-5,6,7,8-tetrahydronaphthalen-2-amine

A mixture of N-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (800mg, 3.88 mmol) in a 10 M solution of hydrochloric acid in MeOH wereheated to reflux for 4 h. After concentration, the residue was basifiedwith 2 N aqueous solution of NaOH to pH 9, then extracted with EtOAc (50mL×2). The organic layer was washed with brine (30 mL), dried, andconcentrated. The residue was dissolved in DMF (20 mL), cooled to 0° C.,and NaH (60% dispersion in mineral oil, 0.155 mg, 3.88 mml) was added inone portion. Iodomethane (582 mg, 3.88 mmol) was added dropwise. Theresulting mixture was stirred at the same temperature for another 2 h.The reaction mixture was quenched by ice (20 g) and then extracted withEtOAc (50 mL×2). The organic layer was washed with brine (20 mL), dried,and concentrated to give a yellow solid (190 mg). ESI MS: m/z 207[M+H]⁻.

e. N²-Methyl-5,6,7,8-tetrahydronaphthalene-1,2-diamine

To a solution of N-methyl-1-nitro-5,6,7,8-tetrahydronaphthalen-2-amine(crude product from the previous step, 190 mg, 0.918 mmol) in MeOH (20mL) was added 10% Pd on carbon (98 mg, 0.0918 mmol) under nitrogen, thenreplaced with hydrogen atmosphere (1 L). The resulting mixture wasstirred at room temperature for 16 h. After filtration through Celite,the filtrate was concentrated and the residue was purified by prep-TLC(DCM/MeOH v/v 10:1) to giveN²-methyl-5,6,7,8-tetrahydronaphthalene-1,2-diamine as a white solid(100 mg, 61% yield). ESI MS: m/z 177 [M+H]⁺

a. tert-Butyl 5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate

A mixture of tert-butyl5-iodo-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (5 g, 13.8mmol), benzylamine (1.776 g, 16.6 mmol),bis(dibenzylideneacetone)palladium (397 mg, 0.79 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (858 mg, 1.38 mmol),and sodium tert-butoxide (2.65 g, 27.6 mmol) in dioxane (50 mL) washeated to 120° C. for 16 h under nitrogen. The mixture was filtered. Thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (PE/EtOAc v/v 1:1) to give tert-butyl5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (3.6g, 76% yield) as a yellow solid. ESI MS: m/z 342 [M+H]⁺.

b. tert-Butyl 5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate

A mixture of tert-butyl5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (3.6g, 10.56 mmol) and 10% Pd on carbon (1.12 g, 1.06 mmol) in MeOH (100 mL)was stirred under hydrogen atmosphere (2 L) at 35° C. for 48 h. Themixture was then filtered through Celite and washed with MeOH (3×25 mL).The combined organic layer was concentrated under reduced pressure. Theresidue was re-dissolved in EtOAc (100 mL) and washed with brine (2×50mL). The combined organic layer was dried over sodium sulfate, filtered,and the solvent removed under reduced pressure. The residue was purifiedby reverse phase column chromatography (eluting with 22% acetonitrile inwater, with 0.1% NH₃.H₂O) to give tert-butyl5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (2.1 g, 79%yield) as a yellow solid. ESI MS: m/z 252 [M+H]⁺.

c. tert-Butyl4-(hydroxymethyl)-5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0^({2,6})]trideca-1(9),2,4,7-tetraene-10-carboxylate

To a solution of tert-butyl5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (2.1 g, 8.37mmol) in 100 mL of THF was added ethyl 3-bromo-2-oxobutanoate (3.482 g,16.74 mmol). The mixture was stirred under reflux overnight. Afterremoval of the solvent, the crude product was purified by silica gelcolumn chromatography (EtOAc/PE v/v 2:1) to give 10-tert-butyl 4-ethyl5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0^({2,6})]trideca-1(9),2,4,7-tetraene-4,10-dicarboxylate(757 mg, 25% yield).

To a solution of 10-tert-butyl 4-ethyl5-methy-13-oxa-3,6,10-triazatricyclo[7.4.0.0^({2,6})]trideca-1(9),2,4,7-tetraene-4,10-dicarboxylate (757 mg,2.09 mmol) in 50 mL of THF was added LAH (2.364 g, 6.27 mmol) at 0° C.The mixture was stirred for 3 h at room temperature. To the mixture wasadded sodium sulfate decahydrate (257 mg) and the mixture was stirredfor 15 min at room temperature. The solid was removed by filtration andthe filtrate was concentrated. The residue was purified by reverse phasecolumn chromatography (eluting with 15% acetonitrile in water, with 0.1%NH₃.H₂O) to give tert-butyl4-(hydroxymethyl)-5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0^({2,6})]trideca-1(9),2,4,7-tetraene-10-carboxylate(630 mg, 94% yield) as a white solid. ESI MS: m/z 320 [M+H]⁺.

a. 5,6,7,8-Tetrahydroisoquinolin-1-amine

To a solution of 5,6,7,8-tetrahydroisoquinoline (5.0 g, 37.6 mmol) inDMF (8 mL) was added sodium amide (2.55 g, 63.9 mmol). The resultingmixture was heated to 170° C. for 16 h and cooled to room temperature.To the mixture was added aqueous 2 N NaOH (50 mL). The mixture wasextracted with DCM (100 mL×3), and the combined organic phase was driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography (eluting with DCM/MeOH v/v 10:1) to give5,6,7,8-tetrahydroisoquinolin-1-amine as a yellow solid (2.6 g, yield46%). ESI MS: m/z 149 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.80 (d, J=5.2Hz, 1H), 6.44 (d, J=5.2 Hz, 1H), 4.34 (br, 2H), 2.67 (t, J=12 Hz, 2H),2.39 (t, J=12 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 2H).

b. Ethyl 2-oxobutanoate

To a solution of 2-oxobutanoic acid (6.0 g, 58.8 mmol) in EtOH (100 mL)was added sulfuric acid (1 mL) at room temperature. The resultingmixture was stirred for 4 h under reflux. The solvent was removed, andthe residue was diluted with water (50 mL) and the pH was adjusted to ˜7with a solution of NaOH (1 N). The mixture was extracted with EtOAc (100mL×3). The combined organic layer was dried over sodium sulfate andconcentrated to give ethyl 2-oxobutanoate (7.5 g, 98% yield). ESI MS:m/z 131 [M+H]⁺.

c. Ethyl 3-bromo-2-oxobutanoate

To a suspension of cupric bromide (14.7 g, 66.9 mmol) in EtOAc (150 mL)was added a solution of ethyl 2-oxobutanoate (2.9 g, 22.3 mmol) inchloroform (75 mL). The mixture was heated at reflux for 18 h and thencooled. The solid was filtered through a short pad of diatomite. Thefiltrate was concentrated and purified by silica gel columnchromatography (EtOAc/PE v/v 1:1) to give ethyl 3-bromo-2-oxobutanoateas a yellow oil (3.2 g, 47% yield). ESI MS: m/z 209 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 5.19 (m, 1H), 4.40 (m, 2H), 1.82 (m, 3H), 1.42 (m, 3H).

d. Ethyl3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline-2-carboxylate

To a solution of 5,6,7,8-tetrahydroisoquinolin-1-amine (444 mg, 3 mmol)in 10 mL of THF was added ethyl 3-bromo-2-oxobutanoate (1.248 g, 6mmol). The mixture was stirred overnight under reflux. After removal ofthe solvent, the crude product was purified by silica gel columnchromatography (EtOAc/PE v/v 4:1) to give ethyl3-methyl-7,8,9,10-tetrahydro imidazo[2,1-a]isoquinoline-2-carboxylate asa white solid (170 mg, 22% yield). ESI MS: m/z 259 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 7.66 (d, J=7.2 Hz, 1H), 6.63 (d, J=7.2 Hz, 1H), 4.48 (q,J=7.2 Hz, 2H), 3.09 (br, 2H), 2.745 (m, 5H), 1.87 (m, 4H), 1.46 (q,J=7.2 Hz, 3H).

e. 3-Methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol

To a solution of ethyl3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline-2-carboxylate(210 mg, 0.81 mmol) in 5 mL of THF was added LAH (920 mg, 2.44 mmol) at0° C. The mixture was stirred for 3 h at room temperature. To themixture was added sodium sulfate decahydrate (100 mg) and the mixturewas stirred for 15 min at room temperature. The solid was removed byfiltration and the filtrate was concentrated to give the crude productof (3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol(200 mg). ESI MS: m/z 217 [M+H]⁺. This crude product was used in thenext step without further purification.

f. 2-(Chloromethyl)-3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline

The crude product of(3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol(200 mg) was dissolved in 5 mL of DCM. To the mixture was added thionylchloride (0.5 mL) at 0° C. The mixture was stirred overnight at roomtemperature. After removal of the solvent, the residue was dried undervacuum to give2-(chloromethyl)-3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline(200 mg). ESI MS: m/z 235 [M+H]⁺.

a. 4-Methoxy-2-methylene-4-oxobutanoic acid

To a solution of 2-methylenesuccinic acid (5.0 g, 38.4 mmol) in MeOH(200 mL) was added p-toluenesulfonamide (100 mg). The mixture wasstirred at 40° C. for 2 days. The mixture was concentrated to dryness.To the residue was added DCM (200 mL). The precipitate was removed byfiltration and the filtrate was concentrated to dryness to give theproduct as a white solid (5.5 g, 99% yield). ESI MS: m/z 145.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 11.17 (bs, 1H), 6.48 (s, 1H), 5.85 (s, 1H),3.71 (s, 3H), 3.36 (s, 2H).

b. 4-Methoxy-2-methyl-4-oxobutanoic acid

To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1.44 g, 10.0mmol) in MeOH (100 mL) was added 10% Pd on carbon (200 mg). The mixturewas stirred under H₂ at room temperature for 2 h. The mixture wasfiltered and the filtrate was concentrated to dryness to give theproduct as a colorless oil (1.4 g, 96% yield). ESI MS: m/z 147.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 3.69 (s, 3H), 2.99-2.94 (m, 1H), 2.77 (d,J=8.0 Hz, 0.5H), 2.73 (d, J=8.4 Hz, 0.5H), 2.46 (d, J=5.6 Hz, 0.5H),2.42 (d, J=6.4 Hz, 0.5H), 1.27 (d, J=7.6 Hz, 3H).

c. Methyl-4-chloro-3-methyl-4-oxobutanoate

To a solution of 4-methoxy-2-methyl-4-oxobutanoic acid (1.2 g, 8.2 mmol)in oxalyl dichloride (15 mL) and DCM (15 mL) was added DMF (20 mg). Themixture was stirred at room temperature for 2 h. The mixture wasconcentrated to dryness to give the product as a yellow solid (1.3 g,96% yield). ¹H NMR (400 MHz, CDCh): δ 3.71 (s, 3H), 3.35-3.30 (m, 1H),2.87 (d, J=8.0 Hz, 0.5H), 2.82 (d, J=8.0 Hz, 0.5H), 2.56 (d, J=5.6 Hz,0.5H) 2.52 (d, J=5.6 Hz, 0.5H), 1.37 (d, J=7.2 Hz, 3H).

d. Methyl 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoate

To a solution of N⁶-methylquinoline-5,6-diamine (914 mg, 5.28 mmol) inDCM (30 mL) was added triethylamine (1.07 g, 10.57 mmol). A solution ofmethyl 4-chloro-3-methyl-4-oxobutanoate (1.3 g, 7.90 mmol) in DCM (10mL) was added dropwise to the above solution over 5 min. The resultingmixture was stirred at room temperature for 20 min. The mixture wasconcentrated to dryness. To the residue was added acetic acid (10 mL).The solution was stirred at 60° C. for 2 h. The solvent was removedunder reduce pressure and to the residue was added saturated sodiumbicarbonate aqueous solution (20 mL). The mixture was extracted with DCM(3×40 mL). The combined organic layer was dried over sodium sulfate,filtered, and concentrated to dryness to give the crude product, whichwas purified by silica gel column chromatography (DCM/MeOH v/v 30:1) togive the title compound as a yellow solid (560 mg 33% yield). ESI MS:m/z 284.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.94-8.88 (m, 2H), 7.95 (d,J=9.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H),3.94 (s, 3H), 3.70-3.63 (m, 4H), 3.28 (d, J=8.4 Hz, 0.5H), 3.23 (d,J=8.4 Hz, 0.5H), 2.86 (d, J=6.0 Hz, 0.5H), 2.82 (d, J=6.0 Hz, 0.5H),1.47 (d, J=6.8 Hz, 3H).

e. 3-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoic acid

To a solution of methyl3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoate (560 mg, 1.97 mmol)in acetonitrile (20 mL) and water (8 mL) was added lithium hydroxidehydrate (249 mg, 5.94 mmol). The mixture was stirred at room temperatureovernight. The mixture was concentrated to about 8 mL. The pH of thesolution was adjusted to ˜4 with 1N HCl aqueous solution. The mixturewas concentrated to dryness and to the residue was added 50 mL ofDCM/MeOH v/v 10:1. The precipitate was removed by filtration and thefiltrate was concentrated to dryness to give the product as a yellowsolid (480 mg, 90% yield). ESI MS: m/z 270.1 [M+H]⁺.

f. 3-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoyl chloride

To a solution of 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoicacid (200 mg, 0.74 mmol) in oxalyl chloride (8 mL) and DCM (8 mL) wasadded DMF (5 mg). The mixture was stirred at room temperature for 2 h.The mixture was concentrated to dryness to give the product as a yellowsolid (160 mg, 75% yield). See, e.g., Indian Journal of Chemistry,Section B: Organic Chemistry Including Medicinal Chemistry, 2000,294-296; Tetrahedron Letters, 2000, 4165-4168.

a. Methyl(Z)-4-(1-amino-3,6-dimethylpyrazin-2(1H)-ylideneamino)-3-methyl-4-oxobutanoate

To a solution of2-imino-3,6-dimethylpyrazin-1(2H)-amine-2,4,6-trimethylbenzene-sulfonate(2 g, 5.92 mmol) in acetonitrile (60 mL) was added triethylamine (1.8 g,17.76 mmol). The mixture was stirred at 50° C. for 30 min. Methyl4-chloro-3-methyl-4-oxobutanoate (1.35 g, 8.23 mmol) was added. Themixture was stirred for an additional 10 min. Then the solution wasevaporated to give 1.1 g of the crude product as a brown solid. ESI MS:m/z 267 [M+H]⁺.

b. Methyl 3-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoate

A solution of(Z)-methyl-4-(1-amino-3,6-dimethylpyrazin-2(1H)-ylideneamino)-3-methyl-4-oxobutanoate(1.10 g, 4.14 mmol) in acetic acid (15 mL) was stirred at 140° C. for 2h in a microwave reactor. The solution was evaporated to give 1.15 g ofthe product as a brown solid. ESI MS: m/z 248 [M+H]⁺.

c. 3-(5,8-Dimethyl[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoic acid

Methyl 3-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoate(1.15 g, 4.64 mmol) in lithium hydroxide aqueous solution (15 mL) wasstirred at room temperature for 16 h. Then the pH of the mixture wasadjusted to 6 with aqueous hydrogen chloride. The mixture wasconcentrated and purified by reverse phase column chromatography(eluting with 15% acetonitrile in water, with 0.1% trifluoroacetic acid)to give the product as a yellow solid (420 mg, 39% yield). ESI MS: m/z235 [M+H]⁺.

d. 3-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoyl chloride

To a solution of3-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoic acid (200mg, 0.086 mmol) in DCM (15 mL) was added oxalyl chloride (3 mL) and DMF(0.1 mL). The mixture was stirred at room temperature for 2 h. Themixture was then evaporated under reduced pressure to give the productas a brown solid (208 mg, 96% yield).

a. 5-Chloro-1,6-naphthyridine

A solution of 1,6-naphthyridin-5(6H)-one (3.2 g, 21.9 mmol) inphosphoryl trichloride (50 mL) was stirred at 100° C. overnight. Thevolatiles were removed under reduced pressure. The residue was cooled to0° C. NaOH (saturated aqueous solution) was added to adjust the pH to 9.The mixture was extracted with EtOAc (200 mL×3). The combined organiclayers were dried over sodium sulfate and concentrated to give 3.3 g ofthe crude product as a yellow solid. ESI MS: m/z 165 [M+H]⁺.

b. 5-Azido-1,6-naphthyridine

To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF(40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture wasstirred at 80° C. for 4 h. The mixture was then poured into water (120mL). The aqueous phase was extracted with EtOAc (150 mL×4). The combinedorganic layers were washed with brine (100 mL×3), dried over sodiumsulfate, and concentrated under reduced pressure to give 3.4 g of thecrude product as a brown solid. ESI MS: m/z 172 [M+H]⁺.

c. 1,6-Naphthyridin-5-amine

To a suspension of 5-azido-1,6-naphthyridine (3.4 g, 19.9 mmol) in MeOH(40 mL) was added hydrochloric acid (30 mL). Stannous chloride dihydrate(22.5 g, 99.5 mmol) was added. The mixture was stirred at 75° C. for 3.5h. A yellow precipitate was formed. The mixture was filtered to give ayellow solid. The solid was suspended in EtOAc (200 mL). NaOH (saturatedaqueous solution) was added to adjust pH to 9. A white precipitate wasformed. The mixture was filtered and the filtrate was extracted withEtOAc (200 mL×6). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure to give 2.0 g of the crude productas a yellow solid. ESI MS: m/z 146 [M+H]⁺.

d. Ethyl 3-bromo-2-oxobutanoate

To a suspension of CuBr₂ (20.6 g, 92.3 mmol) in EtOAc (500 mL) was addeda solution of ethyl 2-oxobutanoate (4.0 g, 30.7 mmol) in 250 mL ofchloroform. The mixture was heated at reflux for 16 h. The mixture wasthen cooled and filtered through a short pad of silica gel. The filtratewas concentrated under reduced pressure to give the product as a lightgreen liquid (3.8 g).

e. Methyl 3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate

A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in THF (25mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). Themixture was stirred at reflux for 36 h. Then the mixture wasconcentrated under reduced pressure, and purified by columnchromatography to give the product as a yellow solid (740 mg, 60%yield). ESI MS: m/z 256.1 [M+H]⁺.

f. (3-Methylimidazo[2,1-f][1,6]naphthyridin-2-yl)methanol

A solution of methyl3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate (100 mg, 0.39mmol) in DCM (8 mL) was cooled to 0° C. DIBAL-H (1 M in cyclohexane, 1.2mL, 1.2 mmol) was added dropwise over 10 min. The mixture was stirred at0° C. for 1 h. 2 mL of saturated ammonium chloride aqueous solution wasadded slowly to quench the reaction. Then 5 mL of saturated sodiumbicarbonate aqueous solution was added. The mixture was extracted withDCM (3×10 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated to give the crude product, which waspurified by column chromatography to give 42 mg of the product as ayellow solid. ESI MS: m/z 214.1 [M+H]⁺.

g. 2-(Chloromethyl)-3-methylimidazo[2,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure W-(f).ESI MS: m/z 232.1 [M+H]⁺.

B. Compounds

The following compounds were prepared using the above procedures.

Compound Methods of No. Structure Preparation Analytical Data  1

J, R LC-MS: m/z 293.1 (MH⁺) @ 1.29 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.04(dt, J = 6.8, 1.2 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.54 (dd, J = 9.2,1.2 Hz, 1H), 7.41 (s, 1H), 7.13 (ddd, J = 8.8, 6.8, 1.2 Hz, 1H), 6.73(td, J = 6.8, 1.6 Hz, 1H), 3.52-3.41 (m, 4H), 2.89 (s, 3H), 2.72 (s,3H).  2

J, S LC-MS: m/z 323.1 (MH⁺) @ 1.27 min; ¹H NMR (CDCl₃, 400 MHz): δ 7.83(d, J = 0.8 Hz, 2H), 3.62 (s, 4H), 2.88 (s, 6H), 2.69 (s, 6H).  3

J, G MS (ESI): m/z 294 (MH⁺); ¹H NMR (CDCl₃, 400 MHz): δ 8.50-8.53 (q, J= 1.2 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.67-7.69 (d, J = 8.8 Hz, 1H),7.46-7.50 (m, 1H), 6.95-6.99 (m, 1H), 3.55-3.61 (m, 4H), 2.87 (s, 3H),2.69 (s, 3H).  4

K LC-MS: m/z 329.2 (MH⁺) @ 1.28 min; ¹H NMR (CDCl₃, 500 MHz): δ8.92-8.89 (m, 2H), 7.96 (d, J = 9.0 Hz, 1H), 7.70-7.66 (m, 1H), 7.69 (d,J = 9.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.34-7.30 (m, 2H), 3.92 (s, 3H),3.71-3.67 (m, 2H), 3.61-3.57 (m, 2H).  5

G, K LC-MS: m/z 329.1 (MH⁺) @ 0.85 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.95(ddd, J = 8.4, 1.6, 0.8 Hz, 1H), 8.89 (dd, J = 4.4, 1.6 Hz, 1H), 8.52(dt, J = 6.8, 1.2 Hz, 1H), 7.95 (dd, J = 9.0, 0.8 Hz, 1H), 7.69 (d, J =9.0 Hz, 2H), 7.53-7.49 (m, 2H), 6.99 (td, J = 6.8, 1.2 Hz, 1H), 3.91 (s,3H), 3.64- 3.59 (m, 4H).  6

J, K LC-MS: m/z 358.1 (MH⁺) @ 1.28 min; ¹H NMR (CD₃OD, 400 MHz): δ 8.93(dd, J = 8.4, 1.2 Hz, 1H), 8.80 (dd, J = 4.8, 2.0 Hz, 1H), 7.93 (ABq,J_(AB) = 9.2 Hz, V_(AB) = 29 Hz, 2H), 7.86 (brd, J = 0.4 Hz, 1H), 7.62(dd, J = 8.4, 4.4 Hz, 1H), 4.02 (s, 3H), 3.65 (m, 4H), 2.79 (s, 3H),2.65 (s, 3H).  7

J, Q LC-MS: m/z 364.0 (MH⁺) @ 1.36 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.42(dd, J = 4.8, 1.2 Hz, 1H), 8.29 (brd, J = 7.2 Hz, 1H), 7.83 (s, 1H),7.35 (dd, J = 8.4, 4.8 Hz, 1H), 3.88 (s, 3H), 3.65-3.60 (m, 2H),3.53-3.49 (m, 2H), 2.87 (s, 3H), 2.69 (s, 3H).  8

E, K LC-MS: m/z 343.1 (MH⁺) @ 1.23 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.98(d, J = 8.8 Hz, 1H), 8.91 (dd, J = 4.4, 1.6 Hz, 1H), 7.85 (ABq, J_(AB) =8.8 Hz, V_(AB) = 108 Hz, 2H), 7.57 (d, J = 6.8 Hz, 1H), 7.53 (dd, J =8.8, 4.4 Hz, 1H), 7.43 (dd, J = 8.8, 6.8 Hz, 1H), 6.81 (d, J = 7.2 Hz,1H), 3.94 (s, 3H), 3.67-3.60 (m, 4H), 2.76 (s, 3H).  9

F, K LC-MS: m/z 343.0 (MH⁺) @ 1.09 min; ¹H NMR (CD₃OD, 400 MHz): δ 9.40(d, J = 8.4 Hz, 1H), 9.11 (dd, J = 5.2, 1.2 Hz, 1H), 8.55 (d, J = 6.8Hz, 1H), 8.26 (ABq, J_(AB) = 9.2 Hz, V_(AB) = 104.4 Hz, 2H), 8.06 (dd, J= 9.2, 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.11 (dd, J = 6.8, 6.8 Hz,1H), 4.16 (s, 3H), 3.81-3.77 (m, 2H), 3.69- 3.31 (m, 2H), 2.57 (s, 3H).10

H, K LC-MS: m/z 358.1 (MH⁺) @ 1.01 min; ¹H NMR (DMSO- d₆, 500 MHz): δ8.85 (d, J = 3.0 Hz, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.02 (s, 1H), 7.92(ABq, J_(AB) = 8.5 Hz, V_(AB) = 92.6 Hz, 2H), 7.58 (dd, J = 8.0, 4.0 Hz,1H), 3.96 (s, 3H), 3.53 (m, 4H), 2.82 (s, 3H), 2.45 (s, 3H). 11

D, K LC-MS: m/z 357.1 (MH⁺) @ 1.06 min; ¹H NMR (CD₃OD, 400 MHz): δ 8.91(d, J = 8.4 Hz, 1H), 8.78 (dd, J = 4.4, 1.2 Hz, 1H), 7.87 (ABq, J_(AB) =4.8 Hz, V_(AB) = 22.3 Hz, 2H), 7.59 (dd, J = 8.4, 4.4 Hz, 1H), 7.29 (d,J = 7.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.61-3.51 (m,4H), 2.601 (s, 3H), 2.50 (s, 3H). 12

J, P LC-MS: m/z 345.1 (MH⁺) @ 1.30 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.91(dd, J = 4.4, 1.2 Hz, 1H), 8.78 (dd, J = 4.8, 0.8 Hz, 1H), 7.97 (ABq,J_(AB) = 10.0 Hz, V_(AB) = 88.2 Hz, 2H), 7.83 (brs, 1H), 7.68 (dd, J =8.4, 4.4 Hz, 1H), 3.66-3.62 (m, 4H), 2.88 (s, 3H), 2.70 (s, 3H). 13

J, M LC-MS: m/z 345.2 (MH⁺) @ 1.40 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.04(dd, J = 4.8, 1.6 Hz, 1H), 8.89 (dd, J = 8.0, 1.6 Hz, 1H), 8.49 (d, J =7.6 Hz, 1H), 7.83 (s, 1H), 7.63 (dd, J = 8.8, 4.8 Hz, 1H), 7.50 (d, J =7.6 Hz, 1H), 3.65-3.61 (m, 4H), 2.88 (s, 3H), 2.70 (s, 3H). 14

E, M LC-MS: m/z 330.1 (MH⁺) @ 1.32 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.03(d, J = 4.0 Hz, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H),7.62 (dd, J = 8.0, 4.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.48 (ABq,J_(AB) = 8.4 Hz, V_(AB) = 67.1 Hz, 2H, 6.79 (d, J = 7.2 Hz, 1H), 3.61(n, 4H), 2.76 (s, 3H). 15

G, M LC-MS: m/z 316.1 (MH⁺) @ 1.24 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.03(dd, J = 4.5, 2.0 Hz, 1H), 8.90 (dd, J = 8.0, 1.5 Hz, 1H), 8.52 (d, J =6.5 Hz, 1H), 8.49 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.61(dd, J = 8.0, 4.5 Hz, 1H), 7.49-7.46 (m, 2H), 6.96 (dt, J = 6.5, 1.0 Hz,1H), 3.62-3.58 (m, 4H). 16

D, M LC-MS: m/z 344.1 (MH⁺) @ 1.48 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.03(dd, J = 4.8, 1.6 Hz, 1H), 8.90 (dd, J = 7.2, 2.0 Hz, 1H), 8.50 (d, J =7.6 Hz, 1H), 7.62 (dd, J = 8.0, 3.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H),7.17 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 3.61 (m, 4H), 2.70(s, 3H), 2.60 (s, 3H). 17

I, M LC-MS: m/z 345.1 (MH⁺) @ 1.23 min: ¹H NMR (CDCl₃, 400 MHz): δ 9.03(d, J = 3.6 Hz, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H),7.63 (dd, J = 8.0, 4.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H),3.62-3.57 (m, 4H), 2.76 (s, 3H), 2.64 (s, 3H). 18

J, K LC-MS: m/z 358.1 (MH⁺) @ 1.36 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.00(dd, J = 4.0, 1.2 Hz, 1H), 8.23 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (s, 1H),7.59 (ABq, J_(AB) = 8.4 Hz, V_(AR) = 34.6, 2H), 7.40 (dd, J = 8.0, 4.4Hz, 1H), 3.94 (s, 3H), 3.83-3.79 (m, 2H), 3.62-3.58 (m, 2H), 2.87 (s,3H), 2.69 (s, 3H). 19

J, L LC-MS: m/z 359.2 (MH⁺) @ 0.99 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.94(d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 7.87 (ABq, J_(AB) = 9.2Hz, V_(AB) = 62.1 Hz, 2H), 7.82 (s, 1H), 3.99 (s, 3H), 3.82 (d, J = 9.6Hz, 1H), 3.80 (d, J = 8.8 Hz, 1H), 3.62 (d, J = 8.8 Hz, 1H), 3.61 (d, J= 9.6 Hz, 1H), 2.87 (s, 3H), 2.69 (s, 3H). 20

G, K LC-MS: m/z 329.0 (MH⁺) @ 1.34 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.01(dd, J = 4.4, 1.6 Hz, 1H), 8.53 (d, J = 6.8 Hz, 1H), 8.23 (dd, J = 8.4,1.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58 (ABq, J_(AB) = 9.2 Hz,V_(AB) = 36.9 Hz, 2H), 7.51-7.46 (m, 1H), 7.39 (dd, J = 8.4, 4.4 Hz,1H), 6.97 (td, J = 8.4, 1.2 Hz, 1H), 3.90 (s, 3H), 3.77-3.73 (m, 2H),3.60- 3.55 (m, 2H). 21

G, L MS (ESI): m/z 330 (MH⁺); ¹H NMR (CDCl₃, 400 MHz): δ 8.95 (d, J = 2Hz, 1H), 8.85 (d, J = 2 Hz, 1H), 8.53 (ddd, J = 0.8, 2.4, 6.8 Hz, 1H),7.95 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz,1H), 7.50 (ddd, J = 1.2, 6.8, 8.4 Hz, 1H), 6.99 (d, J = 1.2, 6.8 Hz,1H), 3.95 (s, 3H), 3.75 (m, 2H), 3.60 (m, 2H). 22

G, O LC-MS: m/z 316.0 (MH⁺) @ 1.22 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.07(dd, J = 4.0, 1.2 Hz, 1H), 8.52 (d, J = 6.8 Hz, 1H), 8.40 (d, J = 7.6Hz, 1H), 8.17 (dd, J = 8.4, 1.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.64(dd, J = 8.0, 4.4 Hz, 1H), 7.50-7.45 (m, 1H), 7.21 (d, J = 7.2 Hz, 1H),6.96 (td, J = 6.8, 1.2 Hz, 1H), 3.65 (brs, 4H). 23

E, N LC-MS: m/z 332.1 (MH⁺) @ 1.27 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.57(d, J = 4.8 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H),7.41 (dd, J = 8.8, 7.2 Hz, 1H), 7.33 (dd, J = 7.6, 5.2 Hz, 1H), 6.79 (d,J = 6.8 Hz, 1H), 4.49 (t, J = 7.2 Hz, 2H), 3.50-3.46 (m, 4H), 3.42-3.37(m, 2H), 2.77 (s, 3H). 24

A, K LC-MS: m/z 357.1 (MH⁺) @ 1.37 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.01(dd, J = 8.4, 1.2 Hz, 1H), 8.92 (dd, J = 4.0, 1.2 Hz, 1H), 7.86 (ABq,J_(AB) = 8.8 Hz, V_(AB) = 115.7 Hz, 2H), 7.56 (s, 1H), 7.55 (dd, J =8.0, 4.4 Hz, 1H), 6.59 (s, 1H), 3.85 (s, 3H), 3.59- 3.49 (m, 4H), 2.65(s, 3H), 2.64 (s, 3H). 25

C, K LC-MS: m/z 357.1 (MH⁺) @ 1.26 min; ¹H NMR (CD₃OD, 400 MHz): δ 8.87(dd, J = 8.0, 0.8 Hz, 1H), 8.72 (dd, J = 4.0, 1.6 Hz, 1H), 7.83 (ABq,J_(AB) = 9.2 Hz, V_(AB) = 21.3, 2H), 7.70 (s, 1H), 7.54 (dd, J = 8.8,4.4 Hz, 1H), 7.48 (brs, 1H), 3.84 (s, 3H), 3.49-3.36 (m, 4H), 2.67 (s,3H), 2.43 (s, 3H). 26

B, K LC-MS: m/z 328.1 (MH⁺) @ 1.31 min; ¹H NMR (CD₃OD, 400 MHz): δ 8.98(dd, J = 8.4, 1.2 Hz, 1H), 8.81 (dd, J = 4.8, 2.0 Hz, 1H), 8.32 (d, J =6.8 Hz, 1H), 7.90 (ABq, J_(AB) = 9.2 Hz, V_(AB) = 15.0 Hz, 2H), 7.64(dd, J = 8.4, 4.0 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.31(ddd, J = 9.2, 6.8, 1.2 Hz, 1H), 6.89 (td, J = 6.8, 0.8 Hz, 1H), 3.86(s, 3H), 3.51-3.47 (m, 2H), 3.39-3.34 (m, 2H). 27

C, M LC-MS: m/z 344.2 (MH⁺) @ 1.21 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.04(dd, J = 4.4, 1.6 Hz, 1H), 8.89 (dd, J = 8.4, 1.6 Hz, 1H), 8.49 (d, J =7.6 Hz, 1H), 7.63 (dd, J = 8.0, 4.4 Hz, 1H), 7.57 (brs, 1H), 7.50 (d, J= 7.2 Hz, 1H), 7.43 (s, 1H), 3.57-3.50 (m, 4H), 2.89 (s, 3H), 2.51 (s,3H). 28

A, K LC-MS: m/z 343.1 (MH⁺) @ 1.37 min; ¹H NMR (CDCl₃, 400 MHz): δ 12.30(brs, 1H), 8.87 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.90 (m, 1H), 7.64(s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 8.4, 4.0 Hz, 1H), 6.62(s, 1H), 3.53 (ddd, J = 18.0, 7.2, 4.0 Hz, 4H), 2.90 (s, 3H), 2.69 (s,3H). 29

Y, K LC-MS: m/z 372.1 (MH⁺) @ 1.36 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.98(d, J = 8.4 Hz, 1H), 8.90 (dd, J = 4.8, 2.0 Hz, 1H), 7.89 (d, J = 9.2Hz, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.4, 4.4Hz, 1H), 4.11 (sxt, J = 7.2 Hz, 1H), 4.0 (s, 3H), 3.73 (dd, J = 14.8,7.6 Hz, 1H), 3.42 (dd, J = 14.8, 7.2 Hz, 1H), 2.85 (s, 3H), 2.66 (s,3H), 1.62 (d, J = 7.2 Hz, 3H). 30

J, X LC-MS: m/z 372.1 (MH⁺) @ 1.36 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.96(dd, J = 8.0, 1.2 Hz, 1H), 8.86 (dd, J = 4.0, 1.6 Hz, 1H), 7.92 (d, J =8.8 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 8.0,4.0 Hz, 1H), 4.00 (sxt, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.80 (dd, J =15.2, 7.2 Hz, 1H), 3.51 (dd, J = 14.8, 6.8 Hz, 1H), 2.83 (s, 3H), 2.62(s, 3H), 1.57 (d, J = 7.2 Hz, 3H). 31

C, K LC-MS: m/z 329.1 (MH⁺) @ 1.22 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.96(dd, J = 4.8, 1.2 Hz, 1H), 8.91 (s, 1H), 8.81 (dd, J = 4.4, 1.6 Hz, 1H),8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.95-7.85 (m, 3H), 7.83 (d, J = 4.4 Hz,1H), 7.63 (dd, J = 8.4, 4.4 Hz, 1H), 3.91 (s, 3H), 3.55-3.45 (m, 4H). 32

C, K LC-MS: m/z 356.1 (MH⁺) @ 1.44 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.97(dd, J = 8.4, 1.2 Hz, 1H), 8.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 (d, J =9.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H),7.24 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.49 (d, J = 6.8 Hz, 1H), 3.80(s, 3H), 3.55-3.44 (m, 4H), 2.61 (s, 3H), 2.51 (s, 3H). 33

A, K LC-MS: m/z 376.1 (MH⁺) @ 1.81 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.97(dd, J = 8.4, 0.8 Hz, 1H), 8.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.96 (d, J =8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H),7.07 (d, J = 7.2 Hz, 1H), 6.54 (s, 1H), 6.51 (dd, J = 7.2, 0.8 Hz, 1H),3.84 (s, 3H), 3.55-3.46 (m, 4H), 2.69 (s, 3H). 34

C, M LC-MS: m/z 343.1 (MH⁺) @ 1.13 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.04(dd, J = 4.4, 1.6 Hz, 1H), 8.90 (dd, J = 8.0, 1.6 Hz, 1H), 8.50 (d, J =7.6 Hz, 1H), 7.63 (dd, J = 7.6, 4.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H),7.32 (s, 1H), 6.94 (brs, 1H), 6.53 (brs, 1H), 3.55-3.45 (m, 4H), 2.62(s, 3H), 2.50 (s, 3H). 35

A, M LC-MS: m/z 344.2 (MH⁺) @ 1.40 min; ¹H NMR (CDCl₃, 400 MHz): δ 9.05(dd, J = 8.4, 1.6 Hz, 1H), 8.90 (dd, J = 8.0, 1.6 Hz, 1H), 8.50 (d, J =7.6 Hz, 1H), 7.63 (dd, J = 8.0, 4.8 Hz, 1H), 7.55 (brs, 1H), 7.51 (d, J= 7.2 Hz, 1H), 6.65 (s, 1H), 3.58-3.45 (m, 4H), 2.69 (s, 3H), 2.62 (s,3H). 36

J, K LC-MS: m/z 344.2 (MH⁺) @ 1.18 min; ¹H NMR (CD₃OD), 400 MHz): δ 8.75(m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.82-7.72 (m, 2H), 7.55 (d, J = 4.4Hz, 1H), 3.56 (brs, 4H), 2.73 (s, 3H), 2.58 (s, 3H). 37

J, U LC-MS: m/z 361.2 (MH⁺) @ 1.35 min; ¹H NMR (CDCl₃, 400 MHz): δ 7.82(s, 1H), 7.00 (ABq, J_(AB) = 8.4 Hz, V_(AB) = 29.6 Hz, 2H), 3.78 (s,3H), 3.61-3.55 (m, 2H), 3.53-3.48 (m, 2H), 3.14 (apt, J = 6.0 Hz, 2H),2.88-2.68 (m, 5H), 2.68 (s, 3H), 1.92-1.83 (m, 4H). 38

J, W LC-MS: m/z 361.1 (MH⁺) @ 2.08 min; ¹H NMR (CDCl₃, 400 MHz): δ 7.80(s, 1H), 7.54 (d, J = 6.8 Hz, 1H), 6.52 (d, J = 6.8 Hz, 1H), 3.48-3.43(m, 2H), 3.39-3.34 (m, 2H), 3.04 (apt, J = 5.6 Hz, 2H), 2.88 (d, J = 0.8Hz, 3H), 2.72 (apt, J = 5.6 Hz, 2H), 2.69 (s, 3H), 2.35 (s, 3H),1.89-1.84 (m, 4H). 39

J, Z LC-MS: m/z 358.1 (MH⁺) @ 1.35 min; ¹H NMR (CDCl₃, 400 MHz): δ8.95-8.85 (m, 1H), 8.86 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H),7.82 (s, 1H), 7.52 (dd, J = 7.6, 5.2 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H),3.56-3.49 (m, 2H), 3.48- 3.39 (m, 2H), 2.89 (s, 3H), 2.71 (s, 3H), 2.48(s, 3H). 40

D, Z LC-MS: m/z 361.1 (MH⁺) @ 1.42 min; ¹H NMR (CDCl₃, 400 MHz): δ 8.89(d, J = 8.0 Hz, 1H), 8.85 (dd, J = 4.4, 1.6 Hz, 1H), 7.88 (d, J = 7.6Hz, 1H), 7.52 (dd, J = 7.6, 4.4 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.14(dd, J = 9.6, 8.0 Hz, 1H), 6.69 (dd, J = 7.6, 4.4 Hz, 1H), 3.52-3.46 (m,2H), 3.45-3.39 (m, 2H), 2.72 (s, 3H), 2.47 (s, 3H). 41

J, V LC-MS: m/z 364.1 (MH⁺) @ 1.28 min; ¹H NMR (CDCl₃, 400 MHz): δ 7.88(s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 4.35 (t, J= 4.4 Hz, 2H), 3.58 (t, J = 4.4 Hz, 2H), 3.38-3.28 (m, 4H), 2.79 (s,3H), 2.68 (s, 3H), 2.33 (s, 3H). 42

J, T LC-MS: m/z 365.1 (MH⁺) @ 1.70 min; ¹H NMR (CDCl₃, 400 MHz): δ 7.82(d, J = 1.2 Hz, 1H), 6.79 (ABq, J_(AB) = 8.4 Hz, V_(AB) = 29.2 Hz, 2H),4.44-4.41 (m, 2H), 4.32-4.29 (m, 2H), 3.75 (s, 3H), 3.69- 3.63 (m, 2H),3.47-3.41 (m, 2H), 2.89 (s, 3H), 2.69 (s, 3H).

C. In Vitro Pharmacology

In one embodiment, the compounds provided herein were assayed for theirability to inhibit human PDE-10A. In one embodiment, the activities ofthe compounds were determined using the Molecular Devices IMAP PDEFluorescence Polarization assay using recombinant human PDE-10 enzymeexpressed in a baculoviral system. Briefly, 10 μL of a compound (0.2nM-20 μM) was added to either a 96-well half area black plate or a384-well black plate along with 10 μL of Fluorescein-labeled cAMP/cGMPsubstrate as per manufacturer's instructions and 10 μL of PDE enzyme(activity 0.1 U). Following a 40-minute incubation at 37° C., 60 μL ofIMAP binding reagent was added. The plate was then read on a PerkinElmer Victor (480-535 nm). The data was analyzed using Prism Software(GraphPad Inc, San Diego, Calif.).

The potency of the compounds provided herein in human PDE-10 inhibitionassay (enzyme assay IC₅₀) is summarized in the table below.

Compound No. PDE-10 IC₅₀ (μM) 1 +++ 2 + 3 + 4 ++ 5 +++ 6 ++++ 7 ++++ 8++++ 9 ++++ 10 +++ 11 ++++ 12 ++ 13 +++ 14 +++ 15 + 16 ++++ 17 +++ 18++++ 19 ++++ 20 ++ 21 ++ 22 + 23 + 24 ++++ 25 +++ 26 + 27 +++ 28 +++ 29++++ 30 +++ 31 + 32 +++ 33 ++++ 34 ++ 35 +++ 36 ++++ 37 ++++ 38 ++++ 39++++ 40 ++++ 41 +++ 42 ++++ IC₅₀ ≤0.01 μM ++++; 0.01 < IC₅₀ ≤ 0.1 μM+++; 0.1 < IC₅₀ ≤ 0.5 μM ++; IC₅₀ >0.5 μM +.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein by reference in their entireties.Citation or identification of any reference in this application is notan admission that such reference is available as prior art to thisapplication. The full scope of the disclosure is better understood withreference to the appended claims.

What is claimed:
 1. A compound of formula (I):A-L-B  (I) or a pharmaceutically acceptable salt or stereoisomerthereof, wherein: A is

each Y is independently CR³; each R³ is independently hydrogen, halogen,cyano, alkyl, trifluoromethyl, aminoalkyl, heteroalkyl, alkenyl, amido,amino, alkoxy, thiol, cycloalkyl, aryl, heterocyclyl, or heteroaryl; Bis

B¹ is NR⁸, O, or S; B² is CR⁹ or N; L is —C(R¹⁰)₂—C(R¹⁰)₂—; R⁴ and R⁵,together with the atoms to which they are attached, form a cycloalkylring, a monocyclic aryl ring, a multicyclic aryl ring, a heterocyclylring, or a heteroaryl ring, each of which is substituted with one ormore R¹²; R⁶ is hydrogen, halogen, cyano, alkyl, aminoalkyl,heteroalkyl, aralkyl, heteroaralkyl, alkenyl, amido, amino, alkoxy,thiol, cycloalkyl, aryl, heterocyclyl, or heteroaryl; R⁷ is hydrogen,alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, orheteroaryl; R⁸ is hydrogen, alkyl, heteroalkyl, alkenyl, cycloalkyl,aryl, heterocyclyl, or heteroaryl; R⁹ is hydrogen, halogen, cyano,alkyl, aminoalkyl, heteroalkyl, aralkyl, heteroaralkyl, alkenyl, amido,amino, alkoxy, thiol, cycloalkyl, aryl, heterocyclyl, or heteroaryl;each R¹⁰ is independently hydrogen; each occurrence of R¹² isindependently (i) hydrogen, halogen, cyano, C(O)R¹³, C(O)NR¹³R¹⁴,C(O)OR¹³, NR¹³R¹⁴, N(R¹³)C(O)R¹⁴, OR¹³, OC(O)R¹³, SR¹³, S(O)R¹³,S(O)₂R¹³, or S(O)₂NR¹³R¹⁴; or (ii) alkyl, heteroalkyl, aralkyl,heteroaralkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; and eachoccurrence of R¹³ and R¹⁴ is independently hydrogen, alkyl, heteroalkyl,aralkyl, heteroaralkyl, cycloakyl, aryl, heterocyclyl, or heteroaryl; orR¹³ and R¹⁴, together with the nitrogen atom to which they are attached,may form a 3 to 10 membered ring.
 2. The compound of claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, wherein eachR³ is independently hydrogen, methyl, ethyl, or trifluoromethyl.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein B is:


4. The compound of claim 3, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein: R⁴ and R⁵, together with the atoms towhich they are attached, form a multicyclic aryl ring; and B is abicyclic ring system.
 5. The compound of claim 3, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein: R⁴ and R⁵, togetherwith the atoms to which they are attached, form a multicyclic aryl ring;and B is a tricyclic ring system.
 6. The compound of claim 5, or apharmaceutically acceptable salt or stereoisomer thereof, wherein B is:

wherein: Ring C is a 5- to 7-membered cycloalkyl ring, a 5- to7-membered heterocyclyl ring, or a 5- or 6-membered heteroaryl ring. 7.The compound of claim 6, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein: R⁸ is hydrogen or methyl; and R⁹ ishydrogen or methyl.
 8. The compound of claim 6, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein each occurrence of R¹²is independently hydrogen.
 9. The compound of claim 1, wherein thecompound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 10. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, and at leastone pharmaceutically acceptable excipient, diluent, or carrier.
 11. Thepharmaceutical composition of claim 10, wherein the pharmaceuticalcomposition further comprises one or more additional active agents. 12.A method for inhibiting phosphodiesterase-10A activity in a subject,comprising administering to a subject in need thereof a therapeuticallyor prophylactically effective amount of a compound of claim 1, or apharmaceutically acceptable salt or stereoisomer thereof.
 13. The methodof claim 12, wherein the subject suffers from a neurological disorder, aschizophrenia-related disorder, a disease having a psychosis component,a psychotic disorder, a behavior disorder, a neurodegenerative disease,a mood disorder, a manic disorder, a movement disorder, a sleepdisorder, an addiction, or an eating disorder.
 14. The method of claim13, wherein the subject suffers from schizophrenia, psychosis,Huntington's disease, depression, or cognitive impairment.
 15. Themethod of claim 12, wherein the subject suffers from schizophrenia,schizophrenia spectrum disorder, schizoaffoctive disorder,schizophreniform disorder, paraphrenia, paranoid personality disorder,schizoid personality disorder, schizotypal personality disorder,delusional disorder, psychosis, psychoaffective disorder, aggression,delirium, Tourette's syndrome, convulsion, seizure, agitation,posttraumatic stress disorder, Huntington's disease, Alzheimer'sdisease, Parkinson's disease, dyskinesia, dementia, bipolar disorder,anxiety, depression, major depressive disorder, dysthymia, affectivedisorder, obsessive-compulsive disorder, attention deficit disorder,attention deficit hyperactivity disorder, vertigo, pain, sensitizationaccompanying neuropathic pain, fibromyalgia, migraine, cognitiveimpairment, cognitive deficit in Alzheimer's disease, cognitive deficitin Parkinson's disease, restless leg syndrome, multiple sclerosis,substance abuse, substance dependency, autism, obesity, undesirableweight retention, undesirable weight gain, metabolic syndrome, diabetes,impaired glucose tolerance, or hyperglycemia.
 16. The method of claim12, wherein the subject suffers from acute schizophrenia, chronicschizophrenia, not otherwise specified schizophrenia, brief psychoticdisorder, Alzheimer's psychosis, Parkinson's psychosis, shared psychoticdisorder, substance-induced psychotic disorder, a psychotic disorder dueto a general medical condition, excitative psychosis, organic psychosis,not otherwise specified psychosis, unipolar depression, treatmentresistant depression, seasonal affective disorder, neuropathic pain,inflammatory pain, cognitive impairment associated with schizophrenia,or non-insulin dependent diabetes.
 17. The method of claim 12, whereinthe method further comprises administering to the subject in needthereof a therapeutically or prophylactically effective amount of asecond active agent.
 18. A method for inhibiting phosphodiesterase-10Aactivity in a subject, comprising administering to a subject in needthereof a therapeutically or prophylactically effective amount of acompound of claim 9, or a pharmaceutically acceptable salt orstereoisomer thereof.